Sulfamoylheleroaryl pyrazole compounds as anti-inflammatory/analgesic agents

ABSTRACT

This invention relates to a compound of the formula:                    
     or a pharmaceutically acceptable salt thereof, wherein A and R 1  are each an optionally substituted 5 to 6-membered heteroaryl, wherein the heteroaryl is optionally fused to a carbocyclic ring or 5 to 6-heteroaryl; R 2  is NH 2 ; R 3  and R 4  are each hydrogen, halo, (C 1 -C 4 )alkyl optionally substituted with halo and the like; and X 1  to X 4  are each hydrogen, halo, hydroxy, (C 1 -C 4 )alkyl optionally substituted with halo and the like. These compounds have COX-2 inhibiting activity and thus useful for treating or preventing inflammation or other COX-2 related diseases.

This application claims the benefit of U.S. Provisional No. 60/168,889,filed on Dec. 3, 1999.

BACKGROUND OF THE INVENTION

This invention relates to sulfamoylheteroaryl pyrazole derivatives andmethods of treatment and pharmaceutical compositions for the treatmentof cyclooxygenase mediated diseases. The compounds of this inventioninhibit the biosynthesis of prostaglandins by intervention of the actionof the enzyme cyclooxygenase on arachidonic acid, and are thereforeuseful in the treatment or alleviation of inflammation and otherinflammation associated disorders, such as arthritis, neurodegenerationand colon cancer, in mammals, preferably humans, dogs, cats orlivestock.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used intreating pain and the signs and symptoms of arthritis because of theiranalgesic and anti-inflammatory activity. It is accepted that commonNSAIDs work by blocking the activity of cyclooxygenase (COX), also knownas prostaglandin G/H synthase (PGHS), the enzyme that convertsarachidonic acid into prostanoids. Prostaglandins, especiallyprostaglandin E₂ (PGE₂), which is the predominant eicosanoid detected ininflammation conditions, are mediators of pain, fever and other symptomsassociated with inflammation. Inhibition of the biosynthesis ofprostaglandins has been a therapeutic target of anti-inflammatory drugdiscovery. The therapeutic use of conventional NSAIDs is, however,limited due to drug associated side effects, including life threateningulceration and renal toxicity. An alternative to NSAIDs is the use ofcorticosteriods, however, long term therapy can also result in severeside effects.

The use of NSAIDs in the treatment or alleviation of inflammation andother inflammation associated disorders in dogs and cats has been morelimited than that in humans: e.g., only three such NSAIDs have beenapproved by the Food and Drug Administration, Committee on VeterinaryMedicine (FDA/CVM), for use in dogs in the United States, i.e.,ETOGESIC® (etodolac), ARQUEL® (meclofenamic acid) and RIMADYL®(carprofen). Consequently, there is less experience and knowledge inveterinary medicine about safety and efficacy issues surrounding the useof NSAIDs in dogs. In veterinary medicine, for example, the most commonindication for NSAIDs is the treatment of degenerative joint disease(DJD), which in dogs often results from a variety of developmentaldiseases, e.g., hip dysplasia and osteochondrosis, as well as fromtraumatic injuries to joints. In addition to the treatment of chronicpain and inflammation, NSAIDs are also useful in dogs for treatingpost-surgical acute pain, as well as for treating clinical signsassociated with osteoarthritis.

Two forms of COX are now known, a constitutive isoform (COX-1) and aninducible isoform (COX-2) of which expression is upregulated at sites ofinflammation (Vane, J. R.; Mitchell, J. A.; Appleton, I.; Tomlinson, A.;Bishop-Bailey, D.; Croxtoll, J.; Willoughby, D. A. Proc. Natl. Acad.Sci. USA, 1994, 91, 2046). COX-1 is thought to play a physiological roleand to be responsible for gastrointestinal and renal protection. On theother hand, COX-2 appears to play a pathological role and is believed tobe the predominant isoform present in inflammation conditions. Apathological role for prostaglandins has been implicated in a number ofhuman disease states including rheumatoid arthritis and osteoarthritis,pyrexia, asthma, bone resorption, cardiovascular diseases, dysmenorrhea,premature labour, nephritis, nephrosis, atherosclerosis, hypotension,shock, pain, cancer, and Alzheimer disease. It is believed thatcompounds that would selectively inhibit the biosynthesis ofprostaglandins by intervention of activity of the enzyme COX-2 onarachidonic acid would provide alternate therapy to the use ofconventional NSAIDs or corticosteriods in that such compounds wouldexert anti-inflammatory effects without the adverse side effectsassociated with COX-1 inhibition.

A variety of sulfonylbenzene compounds which inhibit COX have beendisclosed in patent publications (WO 97/16435, WO 97/14691, WO 96/19469,WO 96/36623, WO 96/03392, WO 96/03387, WO 97/727181, WO 96/936617, WO96/19469, WO 96/08482, WO 95/00501, WO 95/15315, WO 95/15316, WO95/15317, WO 95/15318, WO 97/13755, EP 0799523, EP 418845, and EP554829). Especially, International Publication Number WO 97/11704discloses pyrazole compounds substituted with optionally substitutedaryl.

SUMMARY OF THE INVENTION

The present invention provides a compound of the following formula:

or a pharmaceutically acceptable salt thereof, wherein

A is selected from the group consisting of

a) (5- to 6-membered)-heteroaryl containing 1 to 4 ring heteroatomsindependently selected from —N═, —NR′—, —O—, or —S—, wherein saidheteroaryl is optionally substituted with 1-3 substituents independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino,di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido,(C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—, formyl,(C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl may optionally besubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—;

b) (5- to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S— or—O—; wherein said heteroaryl is fused to a saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring; whereineither of said (5- to 6-membered)-heteroaryl ring or said fusedsaturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring may optionally be substituted with 1 to 2substituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino,di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido,(C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—, formyl,(C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—; and

c) (5- to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S—, or—O—; wherein said heteroaryl is fused to a (5- to 6-membered)-heteroarylcontaining 1 to 2 ring heteroatoms independently selected from the groupconsisting of —N═, —NR′—, —S— or —O—; wherein either of said (5- to6-membered)-heteroaryl or said fused (5- to 6-membered)-heteroaryl isoptionally substituted with one to two substituents per ring, whereinsaid substituents are independently selected from the group consistingof halo, hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ ishydrogen or (C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl mayoptionally be substituted with 1 to 3 substituents independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino,di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido,(C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—, formyl,(C₁-C₄)alkyl-(C═O)— and (C₁-,C₄)alkoxy-(C═O)—;

R¹ is selected from the group consisting of

a) (5- to 6-membered)-heteroaryl containing 1 to 4 ring heteroatomsindependently selected from —N═, —NR—, —O—, or —S—, wherein saidheteroaryl is optionally substituted with 1-3 substituents independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino,di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido,(C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—, formyl,(C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—;

b) (5- to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S— or—O—; wherein said heteroaryl is fused to a saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring; whereineither of said (5- to 6-membered)-heteroaryl ring or said fusedsaturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring is optionally substituted with 1 to 2substituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino,di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido,(C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—, formyl,(C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—; and

c) (5- to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S—, or—O—; wherein said heteroaryl is fused to a (5- to 6-membered)-heteroarylcontaining 1 to 2 ring heteroatoms independently selected from the groupconsisting of —N═, —NR′—, —S— or —O—; wherein either of said (5- to6-membered)-heteroaryl or said fused (5- to 6-membered)-heteroaryl isoptionally substituted with one to two substituents per ring, whereinsaid substituents are independently selected from the group consistingof halo, hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ ishydrogen or (C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxy, cyano, mercapto, carboxy,nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—;

R² is NH₂;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, halo, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-(C═O)—, cyano, nitro, carboxy, (C₁-C₄)alkoxy-(C═O)—,amino-(C═O)—, (C₁-C₄)alkyl-amino-(C═O)—, di[(C₁-C₄)alkyl]-amino-(C═O)—,N-[(C₁-C₄)alkyl]—N-phenyl-amino-(C═O)—, N-[(C₁-C₄)alkyl]-N-[(5- to6-membered)-heteroaryl]-amino-(C═O)—, wherein said (5- to 6—)memberedheteroaryl contains 1 to 4 heteroatoms independently selected from —N═,—NR′—, —O— and —S—; wherein each of said (C₁-C₄)alkyl is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxy, cyano, phenyl, (C₁-C₄)alkoxy and (5-to 6-membered)-heteroaryl containing 1 to 4 heteroatoms independentlyselected from —N═, —NR′—, —O— and —S—; wherein each of said R′ isindependently hydrogen or (C₁-C₄)alkyl; and

X¹, X², X³ and X⁴ are independently selected from the group consistingof hydrogen, halo, hydroxy, cyano, mercapto, carboxy, nitro,(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, (C₁-C₄)alkyl-amino-,di[(C₁-C₄)alkyl]-amino-, (C₁-C₄)alkyl-(C═O)—, (C₁-C₄)alkoxy-(C═O)— andamino-C(═O)—; wherein each said (C₁-C₄)alkyl is optionally substitutedwith 1 to 3 substituents independently selected from the groupconsisting of halo, amino, (C₁-C₄)alkyl-amino-, di[(C₁-C₄)alkyl]-amino-,hydroxy, carboxy, amino-(C═O)—, (C₁-C₄)alkyl-amino-C(═O)—,di[(C₁-C₄)alkyl]-amino-C(═O)—, mercapto, (C₁-C₄)alkyl-S— and(C₁-C₄)alkoxy-(C═O)—.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The compounds of the invention may also exist in different tautomericforms. This invention relates to all tautomers of formula I.

Certain compounds of the invention described herein contain one or moreasymmetric centers and are capable of existing in various stereoisomericforms. The present invention contemplates all such possiblestereoisomers as well as their racemic and resolved, enantiomericallypure forms.

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies or one or more symptoms of such disorder orcondition. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

The term “livestock animals” as used herein refers to domesticatedquadrupeds, which includes those being raised for meat and variousbyproducts, e.g., a bovine animal including cattle and other members ofthe genus Bos, a porcine animal including domestic swine and othermembers of the genus Sus, an ovine animal including sheep and othermembers of the genus Ovis, domestic goats and other members of the genusCapra; domesticated quadrupeds being raised for specialized tasks suchas use as a beast of burden, e.g., an equine animal including domestichorses and other members of the family Equidae, genus Equus, or forsearching and sentinel duty, e.g., a canine animal including domesticdogs and other members of the genes Canis; and domesticated quadrupedsbeing raised primarily for recreational purposes, e.g., members of Equusand Canis, as well as a feline animal including domestic cats and othermembers of the family Felidae, genus Felis.

“Companion animals” as used herein refers to cats and dogs. As usedherein, the term “dog(s)” denotes any member of the species Canisfamiliaris, of which thee are a large number of different breeds. Whilelaboratory determinations of biological activity may have been carriedout using a particular breed, it is contemplated that the inhibitorycompounds of the present invention will be found to be useful fortreating pain and inflammation in any of these numerous breeds. Dogsrepresent a particularly prefered class of patients in that they arewell known as being very susceptible to chronic inflammatory processessuch as osteoarthritis and degenerative joint disease which in dogsoften results from a variety of developmental diseases, e.g., hipdysplasia and osteochondrosis, as well as from traumatic injuries tojoints Conventional NSAIDs, if used in canine therapy, have thepotential for serious adverse gastrointestinal reactions and otheradverse reactions including kidney and live toxicity. Gastrointestinaleffects such as single or multiple ulcerations, including perforationand hemorrhage of the esophagus, stomach, duodenum or small and largeintestine, are usually debilitating, but can often be severe or evenfatal.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, 32P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

This invention also encompasses pharmaceutical compositions containingprodrugs of compounds of the formula I. This invention also encompassesmethods of treating or preventing disorders that can be treated orprevented by the inhibition of matrix metalloproteinases or theinhibition of mammalian reprolysin comprising administering prodrugs ofcompounds of the formula I. Compounds of formula I having free amino,amido, hydroxy, hydroxamic acid, sulfonamide or carboxylic groups can beconverted into prodrugs. Prodrugs include compounds wherein an aminoacid residue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues which are covalently joined through peptidebonds to free amino, hydroxy or carboxylic acid groups of compounds offormula I. The amino acid residues include the 20 naturally occurringamino acids commonly designated by three letter symbols and alsoinclude, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters are covalently bonded to the above substituents offormula I through the carbonyl carbon prodrug sidechain.

One of ordinary skill in the art will appreciate that the compounds ofthe invention are useful in treating a diverse array of diseases. One ofordinary skill in the art will also appreciate that when using thecompounds of the invention in the treatment of a specific disease thatthe compounds of the invention may be combined with various existingtherapeutic agents used for that disease.

For the treatment of rheumatoid arthritis, the compounds of theinvention may be combined with agents such as TNF-α inhibitors such asanti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules(such as Enbrel®), low dose methotrexate, lefunimide,hydroxychloroquine, d-penicilamine, auranofin or parenteral or oralgold.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac; apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib androfecoxib, analgesics and intraarticular therapies such ascorticosteroids and hyaluronic acids such as hyalgan and synvisc.

The active ingredient of the present invention may be administered incombination with inhibitors of other mediators of inflammation,comprising one or more members selected from the group consistingessentially of the classes of such inhibitors and examples thereof whichinclude, matrix metalloproteinase inhibitors, aggrecanase inhibitors,TACE inhibitors, IL-1 processing and release inhibitors, ILra,H₁-receptor antagonists; kinin-B₁- and B₂-receptor antagonists;prostaglandin inhibitors such as PGD-, PGF- PGI₂-, and PGE-receptorantagonists; thromboxane A₂ (TXA2—) inhibitors; 5- and 12-lipoxygenaseinhibitors; leukotriene LTC₄-, LTD₄/LTE₄-, and LTB₄-inhibitors;PAF-receptor antagonists; gold in the form of an aurothio group togetherwith various hydrophilic groups; immunosuppressive agents, e.g.,cyclosporine, azathioprine, and methotrexate; anti-inflammatoryglucocorticoids; penicillamine; hydroxychloroquine; anti-gout agents,e.g., colchicine, xanthine oxidase inhibitors, e.g., allopurinol, anduricosuric agents, e.g., probenecid, sulfinpyrazone, and benzbromarone.

The compounds of the present invention may also be used in combinationwith anticancer agents such as endostatin and angiostatin or cytotoxicdrugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol,taxotere and alkaloids, such as vincristine, and antimetabolites such asmethotrexate.

The compounds of the present invention may also be used in combinationwith anti-hypertensives and other cardiovascular drugs intended tooffset the consequences of atherosclerosis, including hypertension,myocardial ischemia including angina, congestive heart failure, andmyocardial infarction, selected from diuretics, vasodilators such ashydralazine, β-adrenergic receptor antagonists such as propranolol,angiotensin-II converting enzyme inhibitors (ACE-inhibitors) such asenalapril used to treat geriatric mammals with mitral insufficiency, andenalapril alone and in combination with neutral endopeptidaseinhibitors, angiotensin II receptor antagonists such as losartan, renininhibitors, calcium channel blockers such as nifedipine, α₂-adrenergicagonists such as clonidine, α-adrenergic receptor antagonists such asprazosin, and HMG-CoA-reductase inhibitors (anti-hypercholesterolemics)such as lovastatin or atorvastatin.

The active ingredient of the present invention may also be administeredin combination with one or more antibiotic, antifungal, antiprotozoal,antiviral or similar therapeutic agents.

The compounds of the present invention may also be used in combinationwith CNS agents such as antidepressants (such as sertraline),anti-Parkinsonian drugs (such as L-dopa, requip, miratex, MAOBinhibitors such as selegine and rasagiline, comP inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,nicotine agonists, dopamine agonists and inhibitors of neuronal nitricoxide synthase), and anti-Alzheimer's drugs such as donepezil, tacrine,COX-2 inhibitors, propentofylline or metryfonate.

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, droloxifene or fosomax andimmunosuppressant agents such as FK-506 and rapamycin.

The present invention also relates to the formulation of the activeagents of the present invention alone or with one or more othertherapeutic agents which are to form the intended combination, includingwherein said different drugs have varying half-lives, by creatingcontrolled-release forms of said drugs with different release timeswhich achieves relatively uniform dosing; or, in the case of non-humanpatients, a medicated feed dosage form in which said drugs used in thecombination are present together in admixture in said feed composition.There is further provided in accordance with the present inventionco-administration in which the combination of drugs is achieved by thesimultaneous administration of said drugs to be given in combination;including co-administration by means of different dosage forms androutes of administration; the use of combinations in accordance withdifferent but regular and continuous dosing schedules whereby desiredplasma levels of said drugs involved are maintained in the mammals beingtreated, even though the individual mammals making up said combinationare not being administered to said dog simultaneously.

This invention also relates to method for treating or preventingdiseases or conditions mediated by cyclooxygenase-2 in a mammalincluding a human, dog, cat or livestock comprising administering anamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof effective for treating said diseases orconditions to said mammal.

This invention also relates to a pharmaceutical composition comprisingan amount of a compound of formula I or a pharmaceutically acceptablesalt thereof effective for treating or preventing diseases or conditionsmediated by cycloxygenase-2.

More specifically, this invention relates to a pharmaceuticalcomposition for treating a disease or condition selected from the groupconsisting of diseases or conditions in which prostaglandins areimplicated as pathogens, pain, fever, inflammation, rheumatic fever,symptoms associated with influenza and other viral infections, commoncold, low back and neck pain, dysmenorrhea, headache, toothache, sprainsand strains, myositis, neuralgia, synovitis, arthritis includingrheumatoid arthritis, degenerative joint disease or osteoarthritis, goutand ankylosing spondylitis, bursitis, burns, injuries following surgicaland dental procedures, disease or conditions associated with cellularneoplastic transformations and metastic tumor growth, cancer, colorectalcancer, breast and skin cancer, familiar adenomatous polyposis,cyclooxygenase-mediated proliferation disorders, cyclooxygenase-mediatedproliferation disorders in diabetic retinopathy and tumor angiogenesis,prostaniod-induced smooth muscle contraction mediated by synthesis ofcontractile prostanoids, dysmenorrhea, premature labor, asthma,eosinophil related disorders, neurodegenerative diseases, Alzheimer'sand Parkinson's disease, bone loss, osteoarthritis, peptic ulcers,gastritis, regional enterotis, ulcerative colitis, diverticulitis,recurrent of gastrointestinal lesions, gastrointestinal bleeding,coagulation, anemia, hypoprothrombinemia, haemophilia, bleedingproblems; kidney disease and conditions prior to surgery of taking ofanticoagulants.

This invention also relates to a method of treating or preventinginflammatory processes and diseases comprising administering a compoundsof formula I of this invention or its salt to a mammal including ahuman, wherein said inflammatory processes and diseases are defind asabove, and said inhibitory compound is used in combination with one ormore other therapeutically active agents under the following conditions:

A.) where a joint has become seriously inflammed as well as infected atthe same time by bacteria, fungi, protozoa, and/or virus, saidinhibitory compound is administered in combination with one or moreantibiotic, antifungal, antiprotozoal, and/or antiviral therapeuticagents;

B.) where a multi-fold treatment of pain and inflammation is desired,said inhibitory compound is administered in combination with inhibitorsof other mediators of inflammation, comprising one or more membersindependently selected from the group consisting essentially of:

(1) NSAIDs;

(2) H₁-receptor antagonists;

(3) kinin-B₁- and B₂-receptor antagonists;

(4) prostaglandin inhibitors selected from the group consisting of PGD-,PGF-PGI₂-, and PGE-receptor antagonists;

(5) thromboxane A₂ (TXA₂—) inhibitors;

(6) 5-, 12- and 15-lipoxygenase inhibitors;

(7) leukotriene LTC₄-, LTD₄/LTE₄-, and LTB₄-inhibitors;

(8) PAF-receptor antagonists;

(9) gold in the form of an aurothio group together with one or morehydrophilic groups;

(10) immunosuppressive agents selected from the group consisting ofcyclosporine, azathioprine, and methotrexate;

(11) anti-inflammatory glucocorticoids;

(12) penicillamine;

(13) hydroxychloroquine;

(14) anti-gout agents including coichicine; xanthine oxidase inhibitorsincluding allopurinol; and uricosuric agents selected from probenecid,sulfinpyrazone, and benzbromarone;

C.)where older mammals are being treated for disease conditions,syndromes and symptoms found in geriatric mammals, said inhibitorycompound is administered in combination with one or more membersindependently selected from the group consisting essentially of:

(1) cognitive therapeutics to counteract memory loss and impairment;

(2) anti-hypertensives and other cardiovascular drugs intended to offsetthe consequences of atherosclerosis, hypertension, myocardial ischemia,angina, congestive heart failure, and myocardial infarction, selectedfrom the group consisting of:

a.) diuretics;

b.) vasodilators;

c.) β-adrenergic receptor antagonists;

d.) angiotensin-II converting enzyme inhibitors (ACE-inhibitors), aloneor optionally together with neutral endopeptidase inhibitors;

e.) angiotensin II receptor antagonists;

f.) renin inhibitors;

g.) calcium channel blockers;

h.) sympatholytic agents;

i.) α₂-adrenergic agonists;

j.) α-adrenergic receptor antagonists; and

k.) HMG-CoA-reductase inhibitors (anti-hypercholester-olemics);

(3) antineoplastic agents selected from:

a.) antimitotic drugs selected from:

i. vinca alkaloids selected from:

 [1] vinblastine, and

 [2] vincristine;

(4) growth hormone secretagogues;

(5) strong analgesics;

(6) local and systemic anesthetics; and

(7) H₂-receptor antagonists, proton pump inhibitors, and othergastroprotective agents.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl”, as used herein, means a straight or branched saturatedmonovalent hydrocarbon radical including, but not limited to, methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like.

The term “alkoxy”, as used herein, means an alkyl-O group wherein“alkyl” is defined as above.

The term “halo”, as used herein, means fluoro, chloro, bromo or iodo,preferably F or Cl.

The term “(5 to 6-membered)-heteroaryl”, as used herein, unlessotherwise indicated, means a monocyclic aromatic hydrocarbon grouphaving five to six ring atoms comprising one to four heteroatoms eachindependently selected from —N═, —NH—, —[N—(C₁-C₄)alkyl]— —O— and —S—.Examples of the monocyclic ring systems are furyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl,thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like.

The term “(5- to 6-membered)-heteroaryl containing 1 to 2 ringheteroatoms independently selected from the group consisting of —N═,—NR′, —S— or —O—; wherein said heteroaryl is fused to a saturated,partially saturated or aromatic “(5- to 7-membered)-carbocyclic ring,”as used herein, unless otherwise indicated, means a bicyclic aromaticheterocyclic group having a first ring covalently bound to the pyrazolenucleus and containing five to six ring atoms comprising 1 to 2heteroatoms each independently selected from —N═, —NH—,—[N—(C₁-C₄)alkyl]— —O— and —S—; wherein said first ring is fused to asecond ring comprising a (5 to 7 membered)-carbocycle, wherein the 5- to7-members include the carbon atoms common to both rings. Examples ofsaid bicyclic ring systems are benzofuranyl, isobenzofuranyl,benzothiophenyl, isobenzothiophenyl, indolyl, isoindolyl,cyclopentapyridyl, pyranopyrrolyl, indazolyl, indoxazinyl, benzoxazolyl,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, pyridopyridyl andthe like.

The term “(5- to 6-membered)-heteroaryl containing 1 to 2 ringheteroatoms independently selected from the group consisting of —N═,—NR′—, —S—, or —O—; wherein said heteroaryl is fused to a (5- to6-membered)-heteroaryl containing 1 to 2 ring heteroatoms independentlyselected from the group consisting of —N═, —NR′—, —S— or —O—” as usedherein, unless otherwise indicated, means a bicyclic aromaticheterocyclic group having a first ring covalently bound to the pyrrazolenucleus and containing five to six ring atoms comprising one to twoheteroatoms each independently selected from —N═, —NH—,—[N—(C₁-C₄)alkyl]—, —O— and —S—; wherein said first ring is fused to asecond ring comprising a 5 to 7 membered heteroaryl, wherein said second5 to 7 members include the atoms common to both rings. Examples of saidbicyclic ring systems are pyridopyridyl or the like.

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such disorder orcondition. The term “treatment” as used herein refers to the act oftreating, as “treating” is defined immediately above.

An embodiment of the present invention includes compounds of formula I,referred to as the A(a) Group compounds, wherein A is (5- to6-membered)-heteroaryl containing 1 to 4 ring heteroatoms independentlyselected from —N═, —NR′—, —O—, or —S—, wherein said heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxy, cyano, mercapto, carboxy,nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or (C₁-C₄)alkyl; whereineach of said (C₁-C₄)alkyl may optionally be substituted with 1 to 3substituents independently selected from the group consisting of halo,hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl,(C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein preferredA is selected from the group consisting of (5- to 6-membered)-heteroarylcontaining 1 to 4 ring heteroatoms independently selected from —N═,—NR′—, —O—, or —S—, wherein said heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from the groupconsisting of halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl may optionally besubstituted with 1 to 3 halo.

A subgenus of the embodiment of the A(a) group of compounds are thosecompounds (designated the subgenus A(a)-R¹(a)) wherein A is definedabove as A(a) and R¹, referred to hereinafter as R¹(a), is (5- to6-membered)-heteroaryl containing 1 to 4 ring heteroatoms independentlyselected from —N═, —NR′—, —O—, or —S—, wherein said heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxy, cyano, mercapto, carboxy,nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or (C₁-C₄)alkyl; whereineach of said (C₁-C₄)alkyl is optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl,(C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein preferredR′ is selected from the group consisting of (5- to6-membered)-heteroaryl containing 1 to 4 ring heteroatoms independentlyselected from —N═, —NR′—, —O—, or —S—, wherein said heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-(C═O)—, hydroxy, cyano and amino; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl may optionally besubstituted with 1 to 3 halo.

Another subgenus of the embodiment of the A(a) group of compounds arethose compounds (designated the subgenus A(a)—R¹ (b)) wherein A isdefined above as A(a) and R¹, referred to hereinafter as R¹ (b), is (5-to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S— or—O—; wherein said heteroaryl is fused to a saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring; whereineither of said (5- to 6-membered)-heteroaryl ring or said fusedsaturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring is optionally substituted with 1 to 2substituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino,di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido,(C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—, formyl,(C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—; wherein preferred R′ is selected from the groupconsisting of (5- to 6-membered)-heteroaryl containing 1 ring heteroatomselected from the group consisting of —N═, —NR′—, —S— or —O—; whereinsaid heteroaryl is fused to an aromatic (6-membered)-carbocyclic ring;wherein either of said (5- to 6-membered)-heteroaryl ring or said fusedaromatic (6-membered)-carbocyclic ring may optionally be substitutedwith 1 to 2 substituents per ring, wherein said substituents areindependently selected from the group consisting of halo and(C₁-C₄)alkyl; wherein R′ is hydrogen or (C₁-C₄)alkyl.

Another subgenus of the embodiment of the A(a) group of compounds arethose compounds (designated the subgenus A(a)—R¹ (c)) wherein A is asdefined above as A(a) and R¹, referred to hereinafter as R¹ (c), is (5-to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S—, or—O—; wherein said heteroaryl is fused to a (5- to 6-membered)-heteroarylcontaining 1 to 2 ring heteroatoms independently selected from the groupconsisting of —N═, —NR′—, —S— or —O—; wherein either of said (5- to6-membered)-heteroaryl or said fused (5- to 6-membered)-heteroaryl isoptionally substituted with one to two substituents per ring, whereinsaid substituents are independently selected from the group consistingof halo, hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ ishydrogen or (C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxy, cyano, mercapto, carboxy,nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—.

Another embodiment of the invention of the A(a) group of compounds,including the subgenera A(a)—R¹ (a), A(a)—R¹ (b) and A(a)—R¹ (c), arethose compounds wherein A is as defined above as A(a), R¹ is as definedabove as R¹ (a, b or c) and one of R³ or R⁴ is hydrogen (whereinR^(3,4a) refers to R³ as hydrogen and wherein R^(3,4b) refers to R⁴ ashydrogen). Such subgenera can be designated A(a)—R^(3,4a) andA(a)—R^(3,4a), and sub-subgenera A(a)—R¹(a)—R^(3,4a),A(a)—R¹(a)—R^(3,4b), A(a)—R¹(b)—R^(3,4a), A(a)—R¹(b)—R^(3,4b),A(a)—R¹(c)—R^(3,4a) and A(a)—R¹(c)—R^(3,4b)).

Another embodiment of the invention of compounds of the formula A(a)compounds, including the subgenera A(a)—R¹(a), A(a)—R¹ (b), A(a)—R¹ (c),A(a)—R^(3,4a) and A(a)—R^(3,4b) and sub-subgenera A(a)—R¹(a)—R^(3,4a),A(a)—R¹(a)—R^(3,4b), A(a)—R¹(b)—R^(3,4a), A(a)—R¹(b)—R^(3,4b),A(a)—R¹(c)—R^(3,4a) and A(a)—R¹(c)—R^(3,4b), are those compounds whereintwo, three or four of X¹, X², X³ and X⁴ are hydrogen (wherein X^(1-4a)refers to two of X¹-X⁴ as hydrogen, X^(1-4b) refers to three of X¹-X⁴ ashydrogen and X^(1-4c) refers to four of X¹-X⁴ as hydrogen). Suchsubgenera can be designated A(a)—X^(1-4a), A(a)—X^(1-4b), A(a)—X^(1-4c).Such sub-subgenera can be designated A(a)—R¹(a)—X^(1-4a),A(a)—R¹(b)—X^(1-4a), A(a)—R¹(c)—X^(1-4a), A(a)—R^(3,4a)—X^(1-4a) andA(a)—R^(3,4b)—X^(1-4a), A(a)—R¹(a)—X^(1-4b), A(a)—R¹(b)—X^(1-4b),A(a)—R¹(c)—X^(1-4b), A(a)—R^(3,4a)—X^(1-4b) and A(a)—R^(3,4b)—X^(1-4b),A(a)—R¹(a)—X^(1-4c), A(a)—R¹(b)—X^(1-4c), A(a)—R¹(c)—X^(1-4c),A(a)—R^(3,4a)—X^(1-4c) and A(a)—R^(3,4b)—X^(1-4c). Sub-sub-subgenera canbe designated A(a)—R¹(a)—R^(3,4a)—X^(1-4a),A(a)—R¹(a)—R^(3,4b)—X^(1-4a), A(a)—R¹(b)—R^(3,4a)—X^(1-4a),A(a)—R¹(b)—R^(3,4b)—X^(1-4a), A(a)—R¹(c)—R^(3,4a)—X^(1-4a) andA(a)—R¹(c)—R^(3,4b)—X^(1-4a), A(a)—R¹(a)—R^(3,4a)—X^(1-4b),A(a)—R¹(a)—R^(3,4b)—X^(1-4b), A(a)—R¹(b)—R^(3,4a)—X^(1-4b),A(a)—R¹(b)—R^(3,4b)—X^(1-4b), A(a)—R¹(c)—R^(3,4a)—X^(1-4b) andA(a)—R¹(c)—R^(3,4b)—X^(1-4b), A(a)—R¹(a)—R^(3,4a)—X^(1-4c),A(a)—R¹(a)—R^(3,4b)—X^(1-4c), A(a)—R¹(b)—R^(3,4a)—X^(1-4c),A(a)—R¹(b)—R^(3,4b)—X^(1-4c), A(a)—R¹(c)—R^(3,4a)—X^(1-4c) andA(a)—R¹(c)—R^(3,4b)—X^(1-4c).

A group of compounds which is preferred among the A(a) Group compounds,including subgenera A(a)—R¹(a), A(a)—R¹(b), A(a)—R¹(c), are thosecompounds designated subgenera A(a)—R^(3a), and sub-subgeneraA(a)—R¹(a)—R^(3a), A(a)—R¹(b)—R^(3a), A(a)—R¹(c)—R^(3a) including anypreferences) wherein A is as defined above as A(a), R¹ is as definedabove as R¹(a, b or c) and R³ is selected from hydrogen; halo;(C₁-C₄)alkyl optionally substituted with 1 to 3 halo; (C₁-C₄)alkoxy;(C₁-C₄)alkyl-O—C(═O)— and cyano (wherein said preferred R³ is referredto as R^(3a)).

Another group of compounds which is preferred among the A(a) Group ofcompounds, including subgenera A(a)—R¹(a), A(a)—R¹(b), A(a)—R¹(c),A(a)—R^(3a), sub-subgenera A(a)—R¹(a)—R^(3a), A(a)—R¹(b)—R^(3a),A(a)—R¹(c)—R^(3a), are those compounds (designated subgeneraA(a)—R^(4a), and sub-subgenera A(a)—R¹(a)—R^(4a), A(a)—R¹(b)—R^(4a),A(a)—R¹(c)—R^(4a), A(a)—R¹(a)—R^(3a)—R^(4a), A(a)—R¹(b)—R^(3a)—R^(4a),A(a)—R¹(c)—R^(3a)—R^(4a)), wherein A is as defined above as A(a), R¹isas defined above as R¹(a, b or c), R³ is defined above as R^(3a) and R⁴is selected from hydrogen; halo; (C₁-C₄)alkyl optionally substitutedwith 1 to 3 halo; (C₁-C₄)alkoxy; (C₁-C₄)alkyl-O—C(═O)— and cyano(wherein said preferred R⁴ is R^(4a)).

Another group of compounds which is preferred among each A(a) Group ofcompounds, including subgenera A(a)—R¹(a), A(a)—R¹(b), A(a)—R¹(c),A(a)—R^(3a), A(a)—R^(4a), sub-subgenera A(a)—R¹(a)—R^(3a),A(a)—R¹(b)—R^(3a), A(a)—R¹(c)—R^(3a), A(a)—R¹(a)—R^(4a),A(a)—R¹(b)—R^(4a), A(a)—R¹(c)—R⁴, and A(a)—R^(3a)—R^(4a), andsub-sub-subgenera A(a)—R¹(a)—R^(3a)—R^(4a), A(a)—R¹(b)—R^(3a)—R^(4a),A(a)—R¹(c)—R^(3a)—R^(4a)) are those compounds (designated subgeneraA(a)—X^(1-4d) and sub-subgenera A(a)—R¹(a)—X^(1-4d),A(a)—R¹(b)—X^(1-4d), A(a)—R¹(c)—X^(1-4d), A(a)—R^(3a)—X^(1-4d) andA(a)—R^(4a)—X^(1-4d) and sub-sub-subgenera A(a)—R¹(a)—R^(3a)—X^(1-4d),A(a)—R¹(b)—R^(3a)—X^(1-4d), A(a)—R¹(c)—R^(3a)—X^(1-4d),A(a)—R¹(a)—R^(4a)—X^(1-4d), A(a)—R¹(b)—R^(4a)—X^(1-4d),A(a)—R¹(c)—R^(4a)—X^(1-4d), A(a)—R^(3a)—R^(4a)—X^(1-4d), andsub-sub-sub-subgenera A(a)—R¹(a)—R^(3a)—R^(4a)—X^(1-4d),A(a)—R¹(b)—R^(3a)—R^(4a)—X^(1-4d), A(a)—R¹(c)—R^(3a)—R^(4a)—X^(1-4d))wherein X¹ and X² are each independently selected from hydrogen; halo;(C₁-C₄)alkyl optionally substituted with 1 to 3 halo; cyano and(C₁-C₄)alkoxy (wherein X^(1-4d) refers to said preferred X¹ and X²).

A group of compounds which is preferred among each A(a) Group ofcompounds, including subgenera A(a)—R¹(a), A(a)—R¹ (b), A(a)—R¹(c),A(a)—R^(3a), A(a)—R^(4a), sub-subgenera A(a)—R¹(a)—R^(3a),A(a)—R¹(b)—R^(3a), A(a)—R¹(c)—R^(3a), A(a)—R¹(a)—R^(4a),A(a)—R¹(b)—R^(4a), A(a)—R¹(c)—R^(4a), A(a)—R^(3a)—R^(4a), andsub-sub-subgenera A(a)—R¹(a)—R^(3a)—R^(4a), A(a)—R¹(b)—R^(3a)—R^(4a),A(a)—R¹(c)—R^(3a)—R^(4a)) are those compounds (designated subgeneraA(a)—X^(1-4e) and sub-subgenera A(a)—R¹(a)—X^(1-4e),A(a)—R¹(b)—X^(1-4e), A(a)—R¹(c)—X^(1-4e), A(a)—R^(3a)—X^(1-4e) andA(a)—R^(4a)—X^(1-4e) and sub-sub-subgenera A(a)—R¹(a)—R^(3a)—X^(1-4e),A(a)—R¹(b)—R^(3a)—X^(1-4e), A(a)—R¹(c)—R^(3a)—X^(1-4e),A(a)—R¹(a)—R^(4a)—X^(1-4e), A(a)—R¹(b)—R^(4a)—X^(1-4e),A(a)—R¹(c)—R^(4a)—X^(1-4e), A(a)—R^(3a)—R^(4a)—X^(1-4e), andsub-sub-sub-subgenera A(a)—R¹(a)—R^(3a)—R^(4a)—X^(1-4e),A(a)—R¹(b)—R^(3a)—R^(4a)—X^(1-4e), A(a)—R¹(c)—R^(3a)—R^(4a)—X^(1-4e))wherein X³ and X⁴ are each independently selected from hydrogen; halo;(C₁-C₄)alkyl optionally substituted with 1 to 3 halo; cyano and(C₁-C₄)alkoxy (wherein X^(1-4e) refers to said preferred X³ and X⁴).

An embodiment of the present invention includes compounds of formula I,referred to as the A(b) Group compounds, wherein A is (5- to6-membered)-heteroaryl containing 1 to 2 ring heteroatoms independentlyselected from the group consisting of —N═, —NR′—, —S— or —O—; whereinsaid heteroaryl is fused to a saturated, partially saturated or aromatic(5- to 7-membered)-carbocyclic ring; wherein either of said (5- to6-membered)-heteroaryl ring or said fused saturated, partially saturatedor aromatic (5- to 7-membered)-carbocyclic ring may optionally besubstituted with 1 to 2 substituents per ring, wherein said substituentsare independently selected from the group consisting of halo, hydroxy,cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl,(C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ ishydrogen or (C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxy, cyano, mercapto, carboxy,nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—.

A subgenus of the embodiment of the A(b) group of compounds are thosecompounds (designated the subgenus A(b)—R¹(a)) wherein A is definedabove as A(b) and R¹, referred to hereinafter as R¹(a), is (5- to6-membered)-heteroaryl containing 1 to 4 ring heteroatoms independentlyselected from —N═, —NR′—, —O—, or —S—, wherein said heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxy, cyano, mercapto, carboxy,nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or (C₁-C₄)alkyl; whereineach of said (C₁-C₄)alkyl is optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl,(C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein preferredR′ is selected from the group consisting of (5- to6-membered)-heteroaryl containing 1 to 4 ring heteroatoms independentlyselected from —N═, —NR′—, —O—, or —S—, wherein said heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-(C═O)—, hydroxy, cyano and amino; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl may optionally besubstituted with 1 to 3 halo.

Another subgenus of the embodiment of the A(b) group of compounds arethose compounds (designated the subgenus A(b)—R¹(b)) wherein A isdefined above as A(b) and R¹, referred to hereinafter as R¹(b), is (5-to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S— or—O—; wherein said heteroaryl is fused to a saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring; whereineither of said (5- to 6-membered)-heteroaryl ring or said fusedsaturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring is optionally substituted with 1 to 2substituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino,di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido,(C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—, formyl,(C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formnyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—; wherein preferred R′ is selected from the groupconsisting of (5- to 6-membered)-heteroaryl containing 1 ring heteroatomselected from the group consisting of —N═, —NR′—, —S— or —O—; whereinsaid heteroaryl is fused to an aromatic (6-membered)-carbocyclic ring;wherein either of said (5- to 6-membered)-heteroaryl ring or said fusedaromatic (6-membered)-carbocyclic ring may optionally be substitutedwith 1 to 2 substituents per ring, wherein said substituents areindependently selected from the group consisting of halo and(C₁-C₄)alkyl; wherein R′ is hydrogen or (C₁-C₄)alkyl.

Another subgenus of the embodiment of the A(b) group of compounds arethose compounds (designated the subgenus A(b)—R¹ (c)) wherein A is asdefined above as A(b) and R¹, referred to hereinafter as R¹ (c), is (5-to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S—, or—O—; wherein said heteroaryl is fused to a (5- to 6-membered)-heteroarylcontaining 1 to 2 ring heteroatoms independently selected from the groupconsisting of —N═, —NR′—, —S— or —O—; wherein either of said (5- to6-membered)-heteroaryl or said fused (5- to 6-membered)-heteroaryl isoptionally substituted with one to two substituents per ring, whereinsaid substituents are independently selected from the group consistingof halo, hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ ishydrogen or (C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxy, cyano, mercapto, carboxy,nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—.

Another embodiment of the invention of the A(b) group of compounds,including the subgenera A(b)—R¹(a), A(b)—R¹(b) and A(b)—R¹(c), are thosecompounds wherein A is as defined above as A(b), R¹is as defined aboveas R¹(a, b or c) and one of R³ or R⁴ is hydrogen (wherein R^(3,4a),refers to R³ as hydrogen and wherein R^(3,4b) refers to R⁴ as hydrogen).Such subgenera can be designated A(b)—R^(3,4a) and A(b)—R^(3,4b), andsub-subgenera A(b)—R¹(a)—R^(3,4a), A(b)—R¹(a)—R^(3,4b),A(b)—R¹(b)—R^(3,4a), A(b)—R¹(b)—R^(3,4b), A(b)—R¹(c)—R^(3,4a) andA(b)—R¹(c)—R^(3,4b)).

Another embodiment of the invention of compounds of the formula A(b)compounds, including the subgenera A(b)—R¹(a), A(b)—R¹(b), A(b)—R¹(c),A(b)—R^(3,4a) and A(b)—R^(3,4b) and sub-subgenera A(b)—R¹(a)—R^(3,4a),A(b)—R¹(a)—R^(3,4b), A(b)—R¹(b)—R^(3,4a), A(b)—R¹(b)—R^(3,4b),A(b)—R¹(c)—R^(3,4a) and A(b)—R¹(c)—R^(3,4b), are those compounds whereintwo, three or four of X¹, X², X³ and X⁴ are hydrogen (wherein X^(1-4a)refers to two of X¹-X⁴ as hydrogen, X^(1-4b) refers to three of X¹-X⁴ ashydrogen and X^(1-4c) refers to four of X¹-X⁴ as hydrogen). Suchsubgenera can be designated A(b)—X^(1-4a), A(b)—X^(1-4b), A(b)—X^(1-4c).Such sub-subgenera can be designated A(b)—R¹(a)—X^(1-4a),A(b)—R¹(b)—X^(1-4a), A(b)—R¹(c)—X^(1-4a), A(b)—R^(3,4a)—X^(1-4a) andA(b)—R^(3,4b)—X^(1-4a), A(b)—R¹(a)—X^(1-4b), A(b)—R¹(b)—X^(1-4b),A(b)—R¹(c)—X^(1-4b), A(b)—R^(3,4a)—X^(1-4b) and A(b)—R^(3,4b)—X^(1-4b),A(b)—R¹(a)—X^(1-4c), A(b)—R¹(b)—X^(1-4c), A(b)—R¹(c)—X^(1-4c),A(b)—R^(3,4a)—X^(1-4c) and A(b)—R^(3,4b)—X^(1-4c). Sub-sub-subgenera canbe designated A(b)—R¹(a)—R^(3,4a)—X^(1-4a),A(b)—R¹(a)—R^(3,4b)—X^(1-4a), A(b)—R¹(b)—R^(3,4a)—X^(1-4a),A(b)—R¹(b)—R^(3,4b)—X^(1-4a), A(b)—R¹(c)—R^(3,4a)—X^(1-4a) andA(b)—R¹(c)—R^(3,4b)—X^(1-4a), A(b)—R¹(a)—R^(3,4a)—X^(1-4b),A(b)—R¹(a)—R^(3,4b)—X^(1-4b), A(b)—R¹(b)—R^(3,4a)—X^(1-4b),A(b)—R¹(b)—R^(3,4b)—X^(1-4b), A(b)—R¹(c)—R^(3,4a)—X^(1-4b) andA(b)—R¹(c)—R^(3,4b)—X^(1-4b), A(b)—R¹(a)—R^(3,4a)—X^(1-4c),A(b)—R¹(a)—R^(3,4b)—X^(1-4c), A(b)—R¹(b)—R^(3,4a)—X^(1-4c),A(b)—R¹(b)—R^(3,4b)—X^(1-4c), A(b)—R¹(c)—R^(3,4a)—X^(1-4c) andA(b)—R¹(c)—R^(3,4b)—X^(1-4c).

A group of compounds which is preferred among the A(b) Group compounds,including subgenera A(b)—R¹ (a), A(b)—R¹(b), A(b)—R¹(c), are thosecompounds (designated subgenera A(b)—R^(3a), and sub-subgeneraA(b)—R¹(a)—R^(3a), A(b)—R¹(b)—R^(3a), A(b)—R¹(c)—R^(3a) including anypreferences) wherein A is as defined above as A(b), R¹ is as definedabove as R¹ (a, b or c) and R³ is selected from hydrogen; halo;(C₁-C₄)alkyl optionally substituted with 1 to 3 halo; (C₁-C₄)alkoxy;(C₁-C₄)alkyl-O—C(═O)— and cyano (wherein said preferred R³ is referredto as R^(3a)).

Another group of compounds which is preferred among the A(b) Group ofcompounds, including subgenera A(b)—R¹(a), A(b)—R¹(b), A(b)—R¹(c),A(b)—R^(3a), sub-subgenera A(b)—R¹(a)—R^(3a), A(b)—R¹(b)—R^(3a),A(b)—R¹(c)—R^(3a), are those compounds (designated subgeneraA(b)—R^(4a), and sub-subgenera A(b)—R¹(a)—R^(4a), A(b)—R¹(b)—R^(4a),A(b)—R¹(c)—R^(4a), A(b)—R¹(a)—R^(3a)—R^(4a), A(b)—R¹(b)—R^(3a)—R^(4a),A(b)—R¹(c)—R³—R^(4a)), wherein A is as defined above as A(b), R¹ is asdefined above as R¹(a, b or c), R³ is defined above as R^(3a) and R⁴ isselected from hydrogen; halo; (C₁-C₄)alkyl optionally substituted with 1to 3 halo; (C₁-C₄)alkoxy; (C₁-C₄)alkyl-O—C(═O)— and cyano (wherein saidpreferred R⁴ is R^(4a)).

Another group of compounds which is preferred among each A(b) Group ofcompounds, including subgenera A(b)—R¹(a), A(b)—R¹(b), A(b)—R¹(c),A(b)—R^(3a), A(b)—R^(4a), sub-subgenera A(b)—R¹(a)—R^(3a),A(b)—R¹(b)—R^(3a), A(b)—R¹(c)—R^(3a), A(b)—R¹(a)—R^(4a),A(b)—R¹(b)—R^(4a), A(b)—R¹(c)—R^(4a), and A(b)—R^(3a)—R^(4a), andsub-sub-subgenera A(b)—R¹(a)—R^(3a)—R⁴, A(b)—R¹(b)—R^(3a)—R^(4a),A(b)—R¹(c)—R^(3a)—R^(4a)) are those compounds (designated subgeneraA(b)—X^(1-4d) and sub-subgenera A(b)—R¹(a)—X^(1-4d),A(b)—R¹(b)—X^(1-4d), A(b)—R¹(c)—X^(1-4d), A(b)—R^(3a)—X^(1-4d) andA(b)—R^(4a)—X^(1-4d) and sub-sub-subgenera A(b)—R¹(a)—R^(3a)—X^(1-4d),A(b)—R¹(b)—R^(3a)—X^(1-4d), A(b)—R¹(c)—R^(3a)—X^(1-4d),A(b)—R¹(a)—R^(4a)—X^(1-4d), A(b)—R¹(b)—R^(4a)—X^(1-4d),A(b)—R¹(c)—R^(4a)—X^(1-4d), A(b)—R³—R^(4a)—X^(1-4d), andsub-sub-sub-subgenera A(b)—R¹(a)—R³a—R^(4a)—X^(1-4d),A(b)—R(b)—R^(3a)—R^(4a)—X^(1-4d), A(b)—R¹(c)—R^(3a)—R^(4a)—X^(1-4d))wherein X¹ and X² are each independently selected from hydrogen; halo;(C₁-C₄)alkyl optionally substituted with 1 to 3 halo; cyano and(C₁-C₄)alkoxy (wherein X^(1-4d) refers to said preferred X¹ and X²).

A group of compounds which is preferred among each A(b) Group ofcompounds, including subgenera A(b)—R¹(a), A(b)—R¹(b), A(b)—R¹(c),A(b)—R^(3a), A(b)—R^(4a), sub-subgenera A(b)—R¹(a)—R^(3a),A(b)—R¹(b)—R^(3a), A(b)—R¹(c)—R^(3a), A(b)—R¹(a)—R^(4a),A(b)—R¹(b)—R^(4a), A(b)—R¹(c)—R^(4a), A(b)—R^(3a)—R^(4a), andsub-sub-subgenera A(b)—R¹(a)—R^(3a)—R^(4a), A(b)—R¹(b)—R^(3a)—R^(4a),A(b)—R¹(c)—R^(3a)—R^(4a)) are those compounds (designated subgeneraA(b)—X^(1-4e) and sub-subgenera A(b)—R¹(a)—X^(1-4e),A(b)—R¹(b)—X^(1-4e), A(b)—R¹(c)—X^(1-4e), A(b)—R^(3a)—X^(1-4e) andA(b)—R^(4a)—X^(1-4e) and sub-sub-subgenera A(b)—R¹(a)—R^(3a)—X^(1-4e),A(b)—R¹(b)—R^(3a)—X^(1-4e), A(b)—R¹(c)—R^(3a)—X^(1-4e),A(b)—R¹(a)—R^(4a)—X^(1-4e), A(b)—R¹(b)—R^(4a)—X^(1-4e),A(b)—R¹(c)—R^(4a)—X^(1-4e), A(b)—R^(3a)—R⁴—X^(1-4e), andsub-sub-sub-subgenera A(b)—R¹(a)—R^(3a)—R^(4a)—X^(1-4e),A(b)—R¹(b)—R^(3a)—R^(4a)—X^(1-4e), A(b)—R¹(c)—R^(3a)—R^(4a)—X^(1-4e))wherein X³ and X⁴ each independently selected from hydrogen; halo;(C₁-C₄)alkyl optionally substituted with 1 to 3 halo; cyano and(C₁-C₄)alkoxy (wherein X^(1-4e) refers to said preferred X³ and X⁴).

An embodiment of the present invention includes compounds of formula I,referred to as the A(c) Group compounds, wherein A is (5- to6-membered)-heteroaryl containing 1 to 2 ring heteroatoms independentlyselected from the group consisting of —N═, —NR′—, —S—, or —O—; whereinsaid heteroaryl is fused to a (5- to 6-membered)-heteroaryl containing 1to 2 ring heteroatoms independently selected from the group consistingof —N═, —NR′—, —S— or —O—; wherein either of said (5- to6-membered)-heteroaryl or said fused (5- to 6-membered)-heteroaryl isoptionally substituted with one to two substituents per ring, whereinsaid substituents are independently selected from the group consistingof halo, hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ ishydrogen or (C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl mayoptionally be substituted with 1 to 3 substituents independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino,di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido,(C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—, formyl,(C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—.

A subgenus of the embodiment of the A(c) group of compounds are thosecompounds (designated the subgenus A(c)—R¹(a)) wherein A is definedabove as A(c) and R¹, referred to hereinafter as R¹(a), is (5- to6-membered)-heteroaryl containing 1 to 4 ring heteroatoms independentlyselected from —N═, —NR′—, —O—, or —S—, wherein said heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxy, cyano, mercapto, carboxy,nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or (C₁-C₄)alkyl; whereineach of said (C₁-C₄)alkyl is optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl,(C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein preferredR′ is selected from the group consisting of (5- to 6-membered)-heteroaryl containing 1 to 4 ring heteroatoms independently selectedfrom —N═, —NR′—, —O—, or —S—, wherein said heteroaryl is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-(C═O)—, hydroxy, cyano and amino; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl may optionally besubstituted with 1 to 3 halo.

Another subgenus of the embodiment of the A(c) group of compounds arethose compounds (designated the subgenus A(c)—R¹(b)) wherein A isdefined above as A(c) and R¹, referred to hereinafter as R¹(b), is (5-to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S— or—O—; wherein said heteroaryl is fused to a saturated, partiallysaturated or aromatic (5- to 7-membered)-carbocyclic ring; whereineither of said (5- to 6-membered)-heteroaryl ring or said fusedsaturated, partially saturated or aromatic (5- to7-membered)-carbocyclic ring is optionally substituted with 1 to 2substituents per ring, wherein said substituents are independentlyselected from the group consisting of halo, hydroxy, cyano, mercapto,carboxy, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,(C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino,di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido,(C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—, formyl,(C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ is hydrogen or(C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxy, cyano, mercapto, carboxy, nitro,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—; wherein preferred R′ is selected from the groupconsisting of (5- to 6-membered)-heteroaryl containing 1 ring heteroatomselected from the group consisting of —N═, —NR′—, —S— or —O—; whereinsaid heteroaryl is fused to an aromatic (6-membered)-carbocyclic ring;wherein either of said (5- to 6-membered)-heteroaryl ring or said fusedaromatic (6-membered)-carbocyclic ring may optionally be substitutedwith 1 to 2 substituents per ring, wherein said substituents areindependently selected from the group consisting of halo and(C₁-C₄)alkyl; wherein R′ is hydrogen or (C₁-C₄)alkyl.

Another subgenus of the embodiment of the A(c) group of compounds arethose compounds (designated the subgenus A(c)—R¹(c)) wherein A is asdefined above as A(c) and R¹, referred to hereinafter as R¹(c), is (5-to 6-membered)-heteroaryl containing 1 to 2 ring heteroatomsindependently selected from the group consisting of —N═, —NR′—, —S—, or—O—; wherein said heteroaryl is fused to a (5- to 6-membered)-heteroarylcontaining 1 to 2 ring heteroatoms independently selected from the groupconsisting of —N═, —NR′—, —S— or —O—; wherein either of said (5- to6-membered)-heteroaryl or said fused (5- to 6-membered)-heteroaryl isoptionally substituted with one to two substituents per ring, whereinsaid substituents are independently selected from the group consistingof halo, hydroxy, cyano, mercapto, carboxy, nitro, (C₁-C₄)alkyl,(C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)alkyl-S—, amino,(C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido, (C₁-C₄)alkylamido,di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—, (C₁-C₄)alkyl-(C═O)—N(R′)—,formyl, (C₁-C₄)alkyl-(C═O)— and (C₁-C₄)alkoxy-(C═O)—; wherein R′ ishydrogen or (C₁-C₄)alkyl; wherein each of said (C₁-C₄)alkyl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxy, cyano, mercapto, carboxy,nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,(C₁-C₄)alkyl-S—, amino, (C₁-C₄)alkylamino, di[(C₁-C₄)alkyl]amino, amido,(C₁-C₄)alkylamido, di[(C₁-C₄)alkyl]amido, (C₁-C₄)alkyl-(C═O)—O—,(C₁-C₄)alkyl-(C═O)—N(R′)—, formyl, (C₁-C₄)alkyl-(C═O)— and(C₁-C₄)alkoxy-(C═O)—.

Another embodiment of the invention of the A(c) group of compounds,including the subgenera A(c)—R¹(a), A(c)—R¹(b) and A(c)—R¹(c), are thosecompounds wherein A is as defined above as A(c), R¹ is as defined aboveas R¹(a, b or c) and one of R³ or R⁴ is hydrogen (wherein R^(3,4a)refers to R³ as hydrogen and wherein R^(3,4b) refers to R⁴ as hydrogen).Such subgenera can be designated A(c)—R^(3,4a) and A(c)—R^(3,4b), andsub-subgenera A(c)—R¹(a)—R^(3,4a), A(c)—R¹(a)—R^(3,4a),A(c)—R¹(b)—R^(3,4a), A(c)—R¹(b)—R^(3,4b), A(c)—R¹(c)—R^(3,4a) andA(c)—R¹(c)—R^(3,4b)).

Another embodiment of the invention of compounds of the formula A(c)compounds, including the subgenera A(c)—R¹(a), A(c)—R¹(b), A(c)—R¹(c),A(c)—R^(3,4a) and A(c)—R^(3,4b) and sub-subgenera A(c)—R¹(a)—R^(3,4b),A(c)—R¹(a)—R^(3,4b), A(c)—R¹(b)—R^(3,4a), A(c)—R¹(b)—R^(3,4b),A(c)—R¹(c)—R^(3,4a) and A(c)—R¹(c)—R^(3,4b), are those compounds whereintwo, three or four of X¹, X², X³ and X⁴ are hydrogen (wherein X^(1-4a)refers to two of X¹-X⁴ as hydrogen, X^(1-4b) refers to three of X¹-X⁴ ashydrogen and X^(1-4c) refers to four of X¹-X⁴ as hydrogen). Suchsubgenera can be designated A(c)-—X^(1-4a), A(c)—X^(1-4b) A(c)—X^(1-4c).Such sub-subgenera can be designated A(c)—R¹(a)—X^(1-4a),A(c)—R¹(b)—X^(1-4a), A(c)—R¹(c)—X^(1-4a), A(c)—R^(3,4a)—X^(1-4a) andA(c)—R^(3,4b)—X^(1-4a), A(c)—R¹(a)—X^(1-4b), A(c)—R¹(b)—X^(1-4b),A(c)—R¹(c)—X^(1-4b), A(c)—R^(3,4a)—X^(1-4b) and A(c)—R^(3,4b)—X^(1-4b),A(c)—R¹(a)—X^(1-4c), A(c)—R¹(b)—X^(1-4c), A(c)—R¹(c)—X^(1-4c),A(c)—R^(3,4a)—X^(1-4c) and A(c)—R^(3,4b)—X^(1-4c). Sub-sub-subgenera canbe designated A(c)—R¹(a)—R^(3,4a)—X^(1-4a),A(c)—R¹(a)—R^(3,4b)—X^(1-4a), A(c)—R¹(b)—R^(3,4a)—X^(1-4a),A(c)—R¹(b)—R^(3,4b)—X^(1-4a), A(c)—R¹(c)—R^(3,4a)—X^(1-4a) andA(c)—R¹(c)—R^(3,4b)—X^(1-4a), A(c)—R¹(a)—R^(3,4a)—X^(1-4b),A(c)—R¹(a)—R^(3,4b)—X^(1-4b), A(c)—R¹(b)—R^(3,4a)—X^(1-4b),A(c)—R¹(b)—R^(3,4b)—X^(1-4b), A(c)—R¹(c)—R^(3,4a)—X^(1-4b) andA(c)—R¹(c)—R^(3,4b)—X^(1-4b), A(c)—R¹(a)—R^(3,4a)—X^(1-4c),A(c)—R¹(a)—R^(3,4b)—X^(1-4c), A(c)—R¹(b)—R^(3,4a)—X^(1-4c),A(c)—R¹(b)—R^(3,4b)—X^(1-4c), A(c)—R¹(c)—R^(3,4a)—X^(1-4c) andA(c)—R¹(c)—R^(3,4b)—X^(1-4c).

A group of compounds which is preferred among the A(c) Group compounds,including subgenera A(c)—R¹(a), A(c)—R¹(b), A(c)—R¹(c), are thosecompounds (designated subgenera A(c)—R^(3a), and sub-subgeneraA(c)—R¹(a)—R^(3a), A(c)—R¹(b)—R^(3a), A(c)—R¹(c)—R^(3a) including anypreferences) wherein A is as defined above as A(c), R¹ is as definedabove as R¹ (a, b or c) and R³ is selected from hydrogen; halo;(C₁-C₄)alkyl optionally substituted with 1 to 3 halo; (C₁-C₄)alkoxy;(C₁-C₄)alkyl-O—C(═O)— and cyano (wherein said preferred R³ is referredto as R^(3a)).

Another group of compounds which is preferred among the A(c) Group ofcompounds, including subgenera A(c)—R¹(a), A(c)—R¹(b), A(c)—R¹(c),A(c)—R^(3a), sub-subgenera A(c)—R¹ (a)—R^(3a), A(c)—R¹(b)—R^(3a),A(c)—R¹(c)—R^(3a), are those compounds (designated subgeneraA(c)—R^(4a), and sub-subgenera A(c)—R¹(a)—R^(4a), A(c)—R¹(b)—R^(4a),A(c)—R¹(c)—R^(4a), A(c)—R¹(a)—R^(3a)—R^(4a), A(c)—R¹(b)—R^(3a)—R^(4a),A(c)—R¹(c)—R^(3a)—R^(4a)), wherein A is as defined above as A(c), R¹isas defined above as R¹(a, b or c), R³ is defined above as R³ and R⁴ isselected from hydrogen; halo; (C₁-C₄)alkyl optionally substituted with 1to 3 halo; (C₁-C₄)alkoxy; (C₁-C₄)alkyl-O—C(═O)— and cyano (wherein saidpreferred R⁴ is R^(4a)).

Another group of compounds which is preferred among each A(c) Group ofcompounds, including subgenera A(c)—R¹(a), A(c)—R¹ (b), A(c)—R¹(c),A(c)—R^(3a), A(c)—R^(4a), sub-subgenera A(c)—R¹(a)—R^(3a),A(c)—R¹(b)—R^(3a), A(c)—R¹(c)—R^(3a), A(c)—R¹(a)—R^(4a),A(c)—R¹(b)—R^(4a), A(c)—R¹(c)—R^(4a), and A(c)—R^(3a)—R^(4a), andsub-sub-subgenera A(c)—R¹(a)—R^(3a)—R^(4a), A(c)—R¹(b)—R^(3a)—R^(4a),A(c)—R¹(c)—R^(3a)—R⁴,) are those compounds (designated subgeneraA(c)—X¹and sub-subgenera A(c)—R¹(a)—X^(1-4d), A(c)—R¹(b)—X^(1-4d),A(c)—R¹(c)—X^(1-4d), A(c)—R^(3a)—X^(1-4d) and A(c)—R^(4a)—X^(1-4d) andsub-sub-subgenera A(c)—R¹(a)—R^(3a)—X^(1-4d),A(c)—R¹(b)—R^(3a)—X^(1-4d), A(c)—R¹(c)—R^(3a)—X^(1-4d),A(c)—R¹(a)—R^(4a)—X^(1-4d), A(c)—R¹(b)—R^(4a)—X^(1-4d),A(c)—R¹(c)—R^(4a)—X^(1-4d), A(c)—R^(3a)—R^(4a)—X^(1-4d), andsub-sub-sub-subgenera A(c)—R¹(a)—R^(3a)—R^(4a)—X^(1-4d),A(c)—R¹(b)—R^(3a)—R^(4a)—X^(1-4d), A(c)—R¹(c)—R^(3a)—R^(4a)—X^(1-4d))wherein X¹ and X² are each independently selected from hydrogen; halo;(C₁-C₄)alkyl optionally substituted with 1 to 3 halo; cyano and(C₁-C₄)alkoxy (wherein X^(1-4d) refers to said preferred X¹ and X²).

A group of compounds which is preferred among each A(c) Group ofcompounds, including subgenera A(c)—R¹(a), A(c)—R¹(b), A(c)—R¹(c),A(c)—R^(3a), A(c)—R^(4a), sub-subgenera A(c)—R¹(a)—R^(3a),A(c)—R¹(b)—R^(3a), A(c)—R¹(c)—R^(3a), A(c)—R¹(a)—R^(4a),A(c)—R¹(b)—R^(4a), A(c)—R¹(c)—R^(4a), A(c)—R^(3a)—R^(4a), andsub-sub-subgenera A(c)—R¹(a)—R^(3a)—R^(4a), A(c)—R¹(b)—R^(3a)—R^(4a),A(c)—R¹(c)—R^(3a)—R^(4a)) are those compounds (designated subgeneraA(c)—X^(1-4e) and sub-subgenera A(c)—R¹(a)—X^(1-4e),A(c)—R¹(b)—X^(1-4e), A(c)—R¹(c)—X^(1-4e), A(c)—R^(3a)—X^(1-4e) andA(c)—R^(4a)—X^(1-4e) and sub-sub-subgenera A(c)—R¹(a)—R^(3a)—X^(1-4e),A(c)—R¹(b)—R^(3a)—X^(1-4e), A(c)—R¹(c)—R^(3a)—X^(1-4e),A(c)—R¹(a)—R^(4a)—X^(1-4e), A(c)—R¹(b)—R^(4a)—X^(1-4e),A(c)—R¹(c)—R^(4a)—X^(1-4e), A(c)—R^(3a)—R^(4a)—X^(1-4e), andsub-sub-sub-subgenera A(c)—R¹(a)—R³a-R^(4a)—X^(1-4e),A(c)—R¹(b)—R^(3a)—R^(4a)—X^(1-4e), A(c)—R¹(c)—R^(3a)—R^(4a)—X^(1-4e))wherein X³ and X⁴ are each independently selected from hydrogen; halo;(C₁-C₄)alkyl optionally substituted with 1 to 3 halo; cyano and(C₁-C₄)alkoxy (wherein X^(1-4e) refers to said preferred X³ and X⁴).

A preferred group of compounds of this invention consists of thosecompounds of formula I, wherein

is selected from the group consisting of

wherein X is CH or N, and the heteroaryl moiety is unsubstituted, mono-,di- or tri-substituted with substituents independently selected from thegroup consisting of halo and (C₁-C₄)alkyl;

a) R¹is heteroaryl selected from the group consisting of furyl,thiazolyl, oxazolyl, thienyl, tetrazolyl, triazolyl, imidazolyl,benzofuranyl and benzothienyl, wherein said heteroaryl is unsubstituted,mono-, di- or tri-substituted with substituents independently selectedfrom the group consisting of halo and (C₁-C₄)alkyl;

R² is NH₂;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, halo and (C₁-C₄)alkyl optionally substituted with 1 to 3 halo;and

X¹, X², X³ and X⁴ are independently selected from the group consistingof hydrogen, halo, methyl, ethyl, methoxy, trifluoromethyl, amino-C(═O)—and cyano.

A more preferred group of compounds of this invention consists of thosecompounds of formula I, wherein

is selected from the group consisting of

R¹ is selected from furyl, thiazolyl and oxazoleyl;

R² is NH₂;

R³ and R⁴ are each independently selected from hydrogen, chloro, fluoro,ethyl, and trifluoromethyl; and

X¹, X², X³ and X⁴ are independently selected from hydrogen, chloro,fluoro and methyl.

Preferred compounds of this invention include

6-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-pyrdinesulfonamide;

5-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-[5-[3-Chloro-4-(1,3-oxazol-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-{4-Chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide;

5-{5-[4-(1,3-Thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide;

5-{5-Ethyl-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide;

5-[4-Ethyl-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-{4-Fluoro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide;

5-[5-[4-(1,3-Thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-{4-Fluoro-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide;

5-[5-Chloro-4-(1,3-thiazole-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-[5-Chloro-4-(1,3-thiazole-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-[4-Chloro-5-[3-chloro-4-(1,3-thiazol-5-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

6-[5-[3-Methyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-pyridinesulfonamidehydrochloride;

5-[5-[3-Methyl-4-(1,3-thiazol-4-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-(4-Ethyl-5-(3-fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide;and

5-(5-(3-Chloro-4-(2-furyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;or its salts.

An even more preferred compounds of this invention are those compoundsof formula I wherein

is selected from the group consisting of

R¹ is selected from furyl, thiazolyl and oxazolyl;

R² is NH₂;

R³ is trifluoromethyl;

R⁴ is selected from hydrogen, fluoro and ethyl;

X¹ and X² are each independently selected from hydrogen and chloro; andX³ and X⁴ are both hydrogen.

Individual preferred compounds in the group are

5-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-[5-[3-Chloro-4-(1,3-oxazol-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-[4-Ethyl-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-{4-Fluoro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamidehydrochloride;

5-[5-[4-(1,3-Thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-[5-Chloro-4-(1,3-thiazole-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-[5-Chloro-4-(1,3-thiazole-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-[5-[3-Methyl-4-(1,3-thiazol-4-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamide;

5-(4-Ethyl-5-(3-fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide;and

5-(5-(3-Chloro-4-(2-furyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;or its salts.

This invention also relates to method of treating or preventing diseasesor conditions in a mammal, comprising administering a compound offormula I to the mammal, wherein the disease or condition is selectedfrom the group consisting of diseases or conditions in whichprostaglandins are implicated as pathogens, pain, fever, inflammation,rheumatic fever, symptoms associated with influenza and other viralinfections, common cold, low back and neck pain, dysmenorrhea, headache,toothache, sprains and strains, myositis, neuralgia, synovitis,arthritis including rheumatoid arthritis, degenerative joint disease orosteoarthritis, gout and ankylosing spondylitis, bursitis, burns,injuries following surgical and dental procedures, disease or conditionsassociated with cellular neoplastic transformations and metastic tumorgrowth, cancer, colorectal cancer, breast and skin cancer, familiaradenomatous polyposis, cyclooxygenase-mediated proliferation disorders,cyclooxygenase-mediated proliferation disorders in diabetic retinopathyand tumor angiogenesis, prostaniod-induced smooth muscle contractionmediated by synthesis of contractile prostanoids, dysmenorrhea,premature labor, asthma, eosinophil related disorders, neurodegenerativediseases, Alzheimer's and Parkinson's disease, bone loss,osteoarthritis, peptic ulcers, gastritis, regional enterotis, ulcerativecolitis, diverticulitis, recurrent of gastrointestinal lesions,gastrointestinal bleeding, coagulation, anemia, hypoprothrombinemia,haemophilia, bleeding problems; kidney disease and conditions prior tosurgery of taking of anticoagulants.

This invention relates to a method for treating or preventing a diseaseor condition wherein the disease or condition is selected from the groupconsisting of diseases or conditions in which prostaglandins areimplicated as pathogens, pain, fever, inflammation, rheumatic fever,symptoms associated with influenza and other viral infections, commoncold, low back and neck pain, dysmenorrhea, headache, toothache, sprainsand strains, myositis, neuralgia, synovitis, arthritis includingrheumatoid arthritis, degenerative joint disease or osteoarthritis, goutand ankylosing spondylitis, bursitis, burns, injuries following surgicaland dental procedures, disease or conditions associated with cellularneoplastic transformations and metastic tumor growth, cancer, colorectalcancer, breast and skin cancer, familiar adenomatous polyposis,cyclooxygenase-mediated proliferation disorders, cyclooxygenase-mediatedproliferation disorders in diabetic retinopathy and tumor angiogenesis,prostaniod-induced smooth muscle contraction mediated by synthesis ofcontractile prostanoids, dysmenorrhea, premature labor, asthma,eosinophil related disorders, neurodegenerative diseases, Alzheimer'sand Parkinson's disease, bone loss, osteoarthritis, peptic ulcers,gastritis, regional enterotis, ulcerative colitis, diverticulitis,recurrent of gastrointestinal lesions, gastrointestinal bleeding,coagulation, anemia, hypoprothrombinemia, haemophilia, bleedingproblems; kidney disease and conditions prior to surgery of taking ofanticoagulants.

This invention also relates to a pharmaceutical composition for treatingor preventing a disease or condition selected from the group consistingof diseases or conditions in which prostaglandins are implicated aspathogens, pain, fever, inflammation, rheumatic fever, symptomsassociated with influenza and other viral infections, common cold, lowback and neck pain, dysmenorrhea, headache, toothache, sprains andstrains, myositis, neuralgia, synovitis, arthritis including rheumatoidarthritis, degenerative joint disease or osteoarthritis, gout andankylosing spondylitis, bursitis, burns, injuries following surgical anddental procedures, disease or conditions associated with cellularneoplastic transformations and metastic tumor growth, cancer, colorectalcancer, breast and skin cancer, familiar adenomatous polyposis,cyclooxygenase-mediated proliferation disorders, cyclooxygenase-mediatedproliferation disorders in diabetic retinopathy and tumor angiogenesis,prostaniod-induced smooth muscle contraction mediated by synthesis ofcontractile prostanoids, dysmenorrhea, premature labor, asthma,eosinophil related disorders, neurodegenerative diseases, Alzheimer'sand Parkinson's disease, bone loss, osteoarthritis, peptic ulcers,gastritis, regional enterotis, ulcerative colitis, diverticulitis,recurrent of gastrointestinal lesions, gastrointestinal bleeding,coagulation, anemia, hypoprothrombinemia, haemophilia, bleedingproblems; kidney disease and conditions prior to surgery of taking ofanticoagulants.

General Synthesis

Compounds of general formula (I) may be prepared by a variety ofsynthetic routes. Representative preparation procedures are outlinedbelow. Unless otherwise indicated, A, R¹, R², R³, R⁴, X¹, X², X³ and X⁴are as defined herein above.

In a desired reaction step of the processes described hereafter, NH orhydroxy protections and removals of the protecting groups used may becarried out according to known procedures such as those described inProtective Groups in Organic Synthesis edited by T. W. Greene et al.(John Wiley & Sons, 1991). Isolated hydroxy groups can generally beprotected as ethers including t-butyldimethylsilyl ethers, acetals andesters. In general, benzyl-type protecting groups are removed byhydrogenolysis, silyl esthers by reaction with fluoride ions or underslightly acidic conditions and several 2-substituted ethyl ethers can becleaved by beta-elimination reactions.

Scheme 1 illustrates preparation methods of compounds of formula Ithrough pyrazole ring formation.

Route 1 (Acylation and Pyrazole-ring Formation):

Referring to Route 1, a compound of the formula I may be prepared byreacting a diketone compound of formula 1-3 with a hydrazine compound ofthe formula 1-4 in a reaction inert solvent. Suitable solvents used inthis reaction include alcohols such as ethanol, trifluoroethanol,methanol, propanol, isopropanol and butanol; dimethyl sulfoxide (DMSO);N,N-dimethylformamide (DMF); acetic acid; N,N-dimethylacetamide (DMA)and N-methyl-2-pyrrolidinone (NMP). Preferred solvents used in thisreaction are methanol, ethanol and acetic acid. This reaction may beconducted in the presence of a stoichiometric or catalytic amount ofacid such as hydrochloric acid, acetic acid, trifluoroacetic acid,p-toluenesulfonic acid or sulfuric acid, preferably acetic acid.Alternatively, a compound of formula 1-4 may be subjected to thereaction as an acid addition salt such as hydrochloride. This reactionis generally carried out at a temperature from about 0° C. to about 140°C., preferably at about the reflux temperature of the solvent for fromabout 2 to about 20 hours.

A compound of formula 1-3 is prepared from a compound of formula 1-1 byreaction with a compound of the formula 1-2 wherein L is a suitableleaving group in the presence of a suitable base and a reaction inertsolvent. Compounds of formula 1-2 may be subjected to the reaction asesters; or ester equivalents such as acylimidazole; dialkylamide;halides; thioesters or acid anhydride. A compound of formula 1-2 ispreferably used in this reaction as an acylimidazole or ester. Suitablebases used in this reaction include n-butyl lithium, potassium carbonate(K₂CO₃), sodium carbonate (Na₂CO₃), cesium carbonate (Cs₂CO₃), sodiumhydride (NaH), sodium methoxide, potassium-tert-butoxide, lithiumdiisopropylamide (LDA), pyrrolidine, piperidine, lithium1,1,1,3,3,3-hexamethyldisilazane ((Me₃Si₂)₂NLi) and the like. Apreferred base is sodium methoxide. This reaction can be carried out ina solvent such as a di-(alkyl)ether (preferred is methyl tert-butylether), tetrahydrofuran (THF), dimethoxyethane (DME), 1,4-dioxane,methanol, dichloromethane, dimethylformamide (DMF), dimethylacetamide(DMA), or DMSO. Reaction temperature ranges from about −100° to about150° C. preferably from about 0° C. to about 50° C., more preferably atabout room temperature (i.e., from about 20° C. to about 25° C.) forfrom about 0.5 to 20 hours.

Route 2 (R¹-moiety Introduction and Pyrazole-ring Formation):

As illustrated in Route 2, a compound of formula I may also be preparedby (1) a cross-coupling-reaction of a compound of formula 1-5, whereinL′ is a suitable leaving group, with a compound of formula 1-6 followedby (2) pyrazole ring formation with a hydrazine compound of formula 1-4as described herein above. In the cross-coupling reaction, a compound offormula 1-5 may be coupled with compounds of formula 1-6 under reactionconditions known to those skilled in the art. Typical compounds offormula 1-6 used in this reaction include boronic acid (so called Suzukireaction), zinc halide (so called Negishi reaction), and tin (IV)derivatives (so called Stille reaction) and the like (for examples referto Tetrahedron, Vol. 54, pp. 263-303, 1998; S. P. Stanforth). A suitableleaving group L′ includes halogen, such as chloro, bromo or iodo,preferably iodo, or trifluorosulfonyloxy (CF₃SO₃—).

When a compound of formula 1-6 is a boronic acid derivative the reactionis typically run in the presence of a suitable base and a palladiumcatalyst. A suitable base includes, but is not limited to, potassiumhydroxide, thallium hydroxide, sodium or potassium bicarbonate, or analkyl amine such as, but not limited to, triethylamine. Palladiumcatalysts typically employed include, for example,tetrakis(triphenylphosphine)palladium anddichlorobis(triphenylphosphine)palladium. Suitable solvents used in thisreaction include, but is not limited to, benzene, toluene,dimethoxyethane (DME), 1,4-dioxane and dimethylformamide (DMF),preferably DME. Alternatively, the reaction may be conducted in biphasicmedia, for example, DME/water or 1,4-dioxane/water, preferablyDME/water. The reaction is usually carried out at reflux temperature ofsolvent, however, lower or higher temperatures may be employed. Reactiontime is typically for from 10 minutes to several days, usually for from30 minutes to 15 hours.

When a compound of formula 1-6 is a zinc halide derivative the reactionis typically run in a suitable reaction inert solvent in the presence ofa palladium or nickel catalyst. Suitable catalysts include, for example,tetrakis(triphenylphosphine)palladium,tetrakis(triphenylphosphine)nickel,dichlorobis(triphenylphosphine)palladium,dichlorobis(1,1-bis(diphenylphosphino)ferrocene)palladium, ordichlorobis(1,4-bis(diphenylphosphino)butane)palladium. Suitablesolvents used in this reaction include, but is not limited to,tetrahydrofuran (THF), diethylether and dimethoxyethane (DME),preferably THF. The reaction is usually carried out at refluxtemperature of solvent, however, lower or higher temperatures may beemployed. Reaction time is typically for from about 10 minutes toseveral days, usually for from about 30 minutes to 15 hours.

When a compound of formula 1-6 is a tin (IV) derivative, for example,Me₃Sn—R¹ or Bu₃Sn—R¹, the reaction is typically run in a suitablereaction inert solvent in the presence a palladium catalyst. Palladiumcatalysts typically employed include, for example,tetrakis(triphenylphosphine)palladium anddichlorobis(triphenylphosphine)palladium. If necessary, a co-catalystsuch as lithium chloride, ammonium hydroxide or copper(I) bromide may beused. Suitable solvents used in this reaction include, but is notlimited to, benzene, toluene, dimethoxyethane (DME), 1,4-dioxane,tetrahydrofuran (THF) and dimethylformamide (DMF), preferably DME or1,4-dioxane. The reaction is usually carried out at reflux temperatureof solvent, however, lower or higher temperatures may be employed.Reaction time is typically for from 10 minutes to several days, usuallyfor from 30 minutes to 15 hours.

Alternatively, compounds of formula 1-3 may also be prepared byheteroaryl-ring formation on a corresponding acyl phenol, acylhalobenzene or N-formylmethylbenzamide compounds and acylation atpara-position on the phenyl ring. The ring formations include (a)thiazole ring formation; (b) oxazole ring formation; (c) triazole ringformation; and (d) imidazole ring formation.

(a) Thiazole Ring Formation:

The thiazole ring formation can typically be carried out by firstintroducing a leaving group such as halo into the acyl moiety thenreacting the compound thus obtained with either phosphorus pentasulfidein the presence of formamide, or thioacetoamide. These reactions can becarried out in a reaction inert solvent such as dioxane under reflux.

(b) Oxazole Ring Formation:

The oxazole ring formation can typically be carried out by treating a2-halo-1-phenyl-butanone compound in the presence of ammonium formate informic acid under reflux. The oxazole ring formation may also be carriedout treating an N-formylmethylbenzamide compound in the presence oftriphenylphosphine, iodine and triethylamine.

(c) Triazole Ring Formation:

Compounds of formula 1-1 wherein R¹ is triazolyl may be prepared byreacting a cyano benzene compound with trimethylsilyldiazomethane in thepresence of n-butyl lithium in a mixture of hexane and diethyl ether atabout 0° C.

(d) Imidazole Ring Formation:

Compounds of formula I wherein R¹ is imidazolyl may be prepared byreacting a known halomethyl-carbonyl-benzene compound (e.g., thosecompounds described in Justus Liebigs Ann. Chem., 1941, 546, 277 byHerbert) with formamide in water at about 140° C.

The latter acylation may be carried out by methods known to thoseskilled in the art or methods illustrated in Route 1 of Scheme 1.

Starting materials used in the processes in Scheme 1 are known compoundsor readily prepared by methods known to those skilled in the art (e.g.,Collection Czechoslov. Chem. Common. Vol. 37, p. 1721, 1972 by J.Vavrina et al.).

Scheme 2 illustrates an alternate method for preparing compounds offormula I.

Thus, a compound of formula I may also be prepared by a cross-couplingreaction of a compound of formula 2-1, wherein L′ is a suitable leavinggroup, with a compound of formula 1-6. In the cross-coupling reaction, acompound of formula 2-1 may be coupled with compounds of formula 1-6under reaction conditions known to those skilled in the art. Typicalcompounds of formula 1-6 used in this reaction include boronic acid (socalled Suzuki reaction), zinc halide (so called Negishi reaction), andtin (IV) derivatives (so called Stille reaction) and the like (forexamples refer to Tetrahedron, Vol. 54, pp. 263-303, 1998; S. P.Stanforth). A suitable leaving group L′ includes halogen, such aschloro, bromo or iodo, preferably iodo, or trifluorosulfonyloxy(CF₃SO₃—). Procedures typically employed are analogous to thosedescribed herein before in route 2 (Scheme 1).

A compound of formula 2-1 is readily prepared from a compound of formula1-5 and a compound of formula 1-4 according to analogous proceduresillustrated in Scheme 1 described herein before.

In another embodiment, compounds of formula I may be prepared asillustrated in Scheme 3.

Thus, a compound of formula I may also be prepared by a cross-couplingreaction of a compound of formula 3-1, wherein M is a boronic acid(e.g., —B(OH)₂), a zinc halide (e.g., —ZnCl) or a tin (IV) (e.g.,—Sn(n-Bu)₃) derivative, with a compound of formula 3-2, wherein L′ is asuitable leaving group, such as chloro, bromo or iodo, preferably iodo,or trifluorosulfonyloxy (CF₃SO₃—). In the cross-coupling reaction, acompound of formula 3-1 may be coupled with compounds of formula 3-2under reaction conditions known to those skilled in the art. Compoundsof formula 3-1 are readily prepared from compounds of formula 2-1(Scheme 2) by standard metal-halogen exchange reactions known to thoseskilled in the art.

Alternatively, compounds of formula I may be prepared as illustrated inScheme 4.

According to Scheme 4, a pyrazole compound of formula 4-1 may be coupledwith a compound of formula 4-2 wherein X is halo, for example, fluoro,bromo or iodo, to yield a compound of formula I. The coupling reactionis usually carried out in the presence of a suitable base such asn-butyllithium (n-BuLi) sodium hydride, potassium carbonate, cesiumcarbonate, potassium tert-butoxide, triethylamine, pyridine, or thelike. A suitable reaction inert solvent includes, but is not limited to,tetrahydrofuran (THF), dimethoxyethane (DME), dimethyl sulfoxide (DMSO),dimethylformamide (DMF) or toluene. The reaction is usually carried outat reflux temperature of solvent, however, lower or higher temperaturesmay be employed. Reaction time is typically for from 10 minutes toseveral days, usually for from 30 minutes to 15 hours. If desired, acatalyst such as copper (II) oxide or copper (II) bromide may be addedto the reaction mixture. Compounds of formula 4-1 may be preparedaccording to similar procedures illustrated in Scheme 1 described hereinbefore.

Compounds of formula I may also be prepared according to the proceduresillustrated in Scheme 5 through oxidation.

Route 1 (Pyrazole-ring Formation and Oxidation):

According to Route 1, a sulfide compound of formula 5-1 may be oxidizedto the compound of formula I using a suitable oxidizing reagent in areaction inert solvent. This reaction is usually carried out at atemperature from −20° C. to the reflux temperature of the reactionmixture for from about 10 minutes to about 30 hours. Preferably, thereaction may be carried out at a temperature in the range of 0° to 50°C. for from about 1 to 20 hours. Suitable oxidizing reagents includemCPBA (m-chloroperoxybenzoic acid), peracetic acid, hydrogen peroxideand oxone. Preferred is mCPBA. Compounds of formula 5-1 may be preparedaccording to the procedures of Scheme 1 except that a sulfide hydrazinecompound of formula 5-2 is used instead of a sulfonyl hydrazine compoundof formula 1-4.

Route 2 (Oxidation and R¹-moiety Introduction):

According to Route 2, compounds of formula 5-4 may be oxidized tocompounds of formula 5-5 (2-1) and then converted to compounds offormula I by introducing R¹ group. The oxidization of compounds offormula 5-4 may be carried out according to the similar procedures asillustrated in Route 1 (Scheme 5). Compounds of formula 5-5 (2-1) may beconverted to compounds of formula I by coupling reaction with a desiredcoupling reagent comprising R¹ group according to procedures known tothose skilled in the art or similar procedures as illustrated in Scheme1 and the discussed herein before.

Scheme 6 illustrates another preparation methods of compounds of formulaI (Heterocycles, 1990, 31, 1041).

Referring to Scheme 7, a compound of formula I may also be prepared by acoupling reaction of compound of formula 7-1 and a compound of formula7-2 under similar conditions illustrated in Scheme 1 or 2.

Formation of Hydrazine Compounds of Formula 4-1:

Scheme 9 illustrates preparation methods of hydrazine compounds formula4-1 which can be used in the preparation process illustrated in Scheme1.

Route 1 (Thioalkylation and Oxidation):

As illustrated in Route 1, compounds of formula 1-4 can be prepared bysubjecting a compound of the formula 9-1-1 wherein L¹ and L²are leavinggroups to thioalkylation, oxidation and reaction with hydrazine oranhydrous hydrazine. Suitable leaving groups of the compounds used inthis reaction are halo. In this process, compounds of the formula 1-4are prepared from compounds of the formula 9-1-3 by reaction withhydrazine or anhydrous hydrazine in the presence of a polar solvent.Suitable solvents used in this reaction include alcohol, such asethanol, methanol, propanol or butanol; dimethyl sulfoxide (DMSO),N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) orN-methyl-2-pyrrolidinone (MP), preferably an alcohol, most preferablyethanol. This reaction is generally carried out at a temperature fromabout 0° C. to about 140° C., preferably at about the reflux temperatureof the polar solvent. Preferably the product is isolated as a salt, suchas a hydrochloride salt. The reaction time ranges from about 1 hour toabout 1 day. The compound of formula 9-1-3 is prepared from a compoundof formula 9-1-2 by reaction with an oxidizing reagent in the presenceof a solvent. Suitable oxidants include meta-chloroperbenzoic acid,hydrogen peroxide, sodium perborate, or Oxone® (Oxone® is preferred).Suitable solvents or solvent mixtures used in this reaction includemethanol-water, dioxane-water, tetrahydrofuran-water, methylenechloride, or chloroform, preferably methanol-water. Suitabletemperatures for the aforesaid reaction range from about 0° C. to about60° C., preferably the temperature may range from about 20° C. to about25° C. (i.e. room temperature). The reaction is complete within about0.5 hours to about 24 hours, preferably about 16 hours. The compound ofthe formula 9-1-2 is prepared from a compound of formula 9-1-1 bynucleophilic substitution reaction using a sulfur nucleophilic reagentsuch as alkylthiol, dialkyldisulfide, sodium alkylsulfinate, sodiumthioalkoxide or potassium Fthioalkoxide, in the presence or absence of abase in a polar solvent. Suitable bases used in this reaction includesodium hydroxide, triethylamine; alkyllithiums such as n-butyllithium,sec-butyllithium, and tert-butyllithium; and lithium diisopropylamide,and suitable solvents include ethers such as dimethylether; alkanolssuch as methanol, ethanol and tert-butanol; a mixture of an alkanol andwater; THF; benzene; toluene; xylene; DMF; DMSO; dioxane; and1,2-dimethoxyethane. This reaction is generally carried out at atemperature from about −78° C. to 200° C. for from about 1 minute to 3days.

Route 2 (Hydrazine Formation):

Referring to Route 2, compound of the formula 1-4 may be prepared byreaction of a compound the formula 9-2-1 with a suitable reagentfollowed by reduction in an inert solvent or by catalytic hydrogenation.Typical reagents used in the first step include sodium nitrite in anaqueous medium (e.g., hydrochloric acid in water); nitrosyl chloride,nitrogen oxides and nitrile ethers. This reaction is typically carriedout at about 0° C. for from about 1 minute to about 10 hours. Suitablereducing agents used in the subsequent reduction include zincpowder-acetic acid, metal halides such as TiCl₃ or SnCl₂,sodium-ethanol, sodium-aqueous ammonia, lithium aluminum hydride and thelike. Catalytic hydrogenation may be carried out using a catalyst suchas palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO₄),platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride(Wilkinson's catalyst), in an appropriate solvent such as methanol,ethanol, THF, dioxane or ethyl acetate, at a pressure from about 1 toabout 5 atmospheres and a temperature from about 10° C. to about 60° C.The following conditions are preferred: Pd on carbon, methanol at 25° C.and 50 psi of hydrogen gas pressure. This method also provides forintroduction of hydrogen isotopes (i.e., deuterium, or tritium) byreplacing ¹H₂ with ²H₂ or ³H₂ in the above procedure. Compounds offormula 1-4 thus obtained may be isolated as an acid addition salt suchas the hydrochloride salt. Compounds of formula 9-1-1 and 9-2-1 arecommercially available or can be prepared by methods well known to thoseof ordinary skill in the art (e.g., F. Walker et al., J. Chem. Soc.1939, 1948).

Triazine compounds of formula 1-4 can be prepared according to themethods illustrated in Scheme 10. In Scheme 10, triazine compounds offormula 1-4 are represented as compounds of formula 10-5.

Scheme 10 illustrates preparation methods of compounds of formula 10-5from compounds of formula 10-1 by substitution reaction with triflate tocompounds of formula 10-2; reduction to compounds of formula 10-3;oxidation to compounds of formula 10-4; and substitution reaction withhydrazine. Substitution reaction of compounds of formula 10-1 withtriflate can be carried out using trifle anhydride in the presence ofpyridine. Reduction of compounds of formula 10-2 may be carried outusing a suitable reducing reagent such as sodium borohydride or lithiumaluminum hydride. Oxidation of compounds of formula 10-3 may be carriedout by using mCPBA or Oxone as described in Scheme 5 and its discussion.Reaction with compounds of formula 10-4 and hydrazine can be carried outin an alcoholic solvent. Compounds of formula 10-5 thus obtained may besubjected to reactions with diketone compounds as illustrated in Scheme1 using a acid catalyst such as sulfuric acid in 2,2,2-trifluoroethanolunder reflux to yield compounds of formula I. In the process illustratedin Scheme 10, halogen can be also introduced to compounds of formula10-2 instead of triflate under known conditions such as chlorinationusing phosphoryl oxychloride. Compounds of formula 10-1 may be preparedby known procedures described in literature such as J. Org. Chem., Vol.63, p. 6329, 1998.

Scheme 11 illustrates preparation methods for synthesizing compounds offormula 11-3, which can be subjected to reactions illustrated in Scheme9.

Referring to Scheme 11, a dicarbonyl compound of formula 11-1, wherein Xis NH (i.e., pyrimidine compounds) or CH (i.e., pyridine compounds) andL² is a leaving group, may be subjected to substitution reaction tointroduce L¹ to give the compound of formula 11-2 followed by reductionto give the compound of formula 11-3. Typical leaving groups L¹ and L²are halo, which can be introduced by halogenation according to methodsknown for those skilled in the art. For example, chlorination of acompound of formula 11-1 can be carried out using a chlorinating reagentsuch as an excess amount of phosphoryl chloride in the presence orabsence of a base such as N,N-diethylaniline. This reaction cantypically be carried out under reflux for from about 30 minutes to about10 hours. The subsequent reduction of compounds of formula 11-2 may becarried out using a reducing reagent such as a metal catalyst in thepresence of a base in a reaction inert solvent according to knownmethods in the art. For example, this reaction can typically be carriedout using zinc powder in the presence of ammonia in a reaction inertsolvent such as benzene at about room temperature for from about 1 hourto about 1 day. Then, compounds of formula 11-3 thus obtained can besubjected to the reactions illustrated in Scheme 9.

Scheme 12 illustrates the other hydrazine preparation methods.

The starting materials in the aforementioned general syntheses may beobtained by conventional methods known to those skilled in the art. Thepreparation of such starting materials is described within theaccompanying non-limiting examples which are provided for the purpose ofillustration only. Alternatively, requisite starting materials may beobtained by analogous procedures, or modifications thereof, to thosedescribed hereinafter.

In each reaction described above, unless indicated otherwise, thereaction pressure is not critical. Generally, the reactions will beconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere).

The starting materials in the aforementioned general syntheses may beobtained by conventional methods known to those skilled in the art. Thepreparation of such starting materials is described within theaccompanying non-limiting examples which are provided for the purpose ofillustration only. Alternatively, requisite starting materials may beobtained by analogous procedures, or modifications thereof, to thosedescribed hereinafter.

The products which are addressed in the aforementioned general synthesesand illustrated in the experimental examples described herein after maybe isolated by standard methods and purification can be achieved byconventional means known to those skilled in the art, such asdistillation, crystallization or chromatography techniques.

Certain compounds described herein contain one or more asymmetriccenters and are capable of existing in various stereoisomeric forms. Thepresent invention contemplates all such possible stereoisomers as wellas their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

In addition, when the compounds of this invention form hydrates orsolvates they are also within the scope of this invention.

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, e.g.,where R³ includes a COOH or tetrazole moiety, are capable of formingbase salts with various pharmacologically acceptable cations. Examplesof such salts include the alkali metal or alkaline-earth metal salts andparticularly, the sodium and potassium salts. These salts are allprepared by conventional techniques. The chemical bases which are usedas reagents to prepare the pharmaceutically acceptable base salts ofthis invention are those which form non-toxic base salts with the hereindescribed acidic compounds of formula I. These non-toxic base saltsinclude those derived from such pharmacologically acceptable cations assodium, potassium, calcium and magnesium, etc. These salts can easily beprepared by treating the corresponding acidic compounds with an aqueoussolution containing the desired pharmacologically acceptable cations,and then evaporating the resulting solution to dryness, preferably underreduced pressure. Alternatively, they may also be prepared by mixinglower alkanolic solutions of the acidic compounds and the desired alkalimetal alkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction and maximum product yields.

Also included within the scope of this invention are bioprecursors (alsocalled pro-drugs) of the compounds of the formula I. A bioprecursor of acompound of the formula I is a chemical derivative thereof which isreadily converted back into the parent compound of the formula I inbiological systems. In particular, a bioprecursor of a compound of theformula I is converted back to the parent compound of the formula Iafter the bioprecursor has been administered to, and absorbed by, amammalian subject, e.g., a human subject.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assay. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of presentationand detectability. Further, substitution with heavier isotopes such asdeutrium, i.e., ²H, can afford therapeutic advantage resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirement and, hence, may be preferred in somecircumstances. Isotopically labelled compounds of formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedure disclosed in above-disclosed Schemes and/or Examples andPreparations below, by submitting a readily available isotopicallylabelled reagent for a non-isotopically labeled reagent.

The compounds of the formula I of this invention can be administered viaeither the oral, parenteral or topical routes to mammals. In general,these compounds are most desirably administered to humans in dosesranging from 0.01 mg to 100 mg per kg of body weight per day, althoughvariations will necessarily occur depending upon the weight, sex andcondition of the subject being treated, the disease state being treatedand the particular route of administration chosen. However, a dosagelevel that is in the range of from 0.1 mg to 10 mg per kg of body weightper day, single or divided dosage is most desirably employed in humansfor the treatment of abovementioned diseases.

These compounds are most desirably administered to said non-humanmammals, e.g. dogs, cats, horses or livestock in an amount, expressed asmg per kg of body weight of said member per day, ranging from about 0.01mg/kg to about 20.0 mg/kg/day, preferably from about 0.1 mg/kg to about12.0 mg/kg/day, more preferably from about 0.5 mg/kg to about 10.0mg/kg/day, and most preferably from about 0.5 mg/kg to about 8.0mg/kg/day.

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents byeither of the above routes previously indicated, and such administrationcan be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of the invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, trochees, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the therapeutically-effective compounds of this inventionare present in such dosage forms at concentration levels ranging 5% to70% by weight, preferably 10% to 50% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatine capsules; preferred materials in this connectionalso include lactose or milk sugar as well as high molecular weightpolyethylene grycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various combinations thereof.

For parenteral administration, solutions of a compound of the presentinvention in either sesame or peanut oil or in aqueous propylene glycolmay be employed. The aqueous solutions should be suitably buffered(preferably pH>8) if necessary and the liquid diluent first renderedisotonic. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intra-articular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

The compounds of formula I may also be administered in the form ofsuppositories for rectal or vaginal administration of the activeingredient. These compositions can be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atroom temperature (for example, 10° C. to 32° C.) but liquid at therectal temperature and will melt in the rectum or vagina to release theactive ingredient. Such materials are polyethylene glycols, cocoabutter, suppository and wax.

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

Combination With Other Drugs:

Compounds of formula I would be useful for, but not limited to, thetreatment of inflammation in a subject, and for treatment of otherinflammation-associated disorders, such as, as an analgesic in thetreatment of pain and headaches, or as an antipyretic for the treatmentof fever. For example, combinations of the invention would be useful totreat arthritis, including but not limited to rheumatoid arthritis,spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis. Such combinations of the inventionwould be useful in the treatment of asthma, bronchitis, inmenstrualcramps, tendinitis, bursitis, and skin related conditions such aspsoriasis, eczema, burns and dermatitis. Combinations of the inventionalso would be useful to treat gastrointestinal conditions such asinflammatory bowel disease. Crohn's disease, gastritis, irritable bowelsyndrome and ulcerative colitis and for the prevention of colorectalcancer. Combinations of the invention would be useful in creatinginflammation in such diseases as vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis,multiple sclercsis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, hypersensitivity, Conjunctivitis, swellingoccurring after injury, myocardial ischemia, and the like. Thecombinations would also be useful for the treatment of certain centralnervous system disorders such as Alzheimer's disease and dimentia. Thecombinations of the invention are useful as anti-inflammatory agents,such as for the treatment of arthritis, with the additional benefit ofhaving significantly less harmful side effects. These compositions wouldalso be useful in the treatment of allergic rhinitis, respiratorydistress syndrome, endotoxin shock syndrome, atherosclerosis and centralnervous system damage resulting from stroke, ischemia and trauma.

Compounds of formula I will be useful as a partial or completesubstitute for conventional NSAID's in preparations wherein they arepresently co-administered with other agents or ingredients. Thus, theinvention encompasses pharmaceutical compositions for treating COX-2mediated diseases as defined above comprising a non-toxictherapeutically effective amount of the compound of formula I and one ormore ingredients such as another pain reliever including acetaminophenor phenacetin; a potentiator including caffeine; an H₂-antagonist,aluminom or magnesium hydroxide, simethicone, a decongestant includingphenylephrine, phenylproanolamine, psuedophedrine, oxymetazoline,ephinephrine, naphazoline, xylometazoline, propylhexedrine, orlevodesoxyephedrine; an antiitussive including codeine, hydrocodone,caramiphen, carbetapentane, or dextramethorphan; a prostaglandinincluding misoprostol, enprostil, rioprostil, ornoprotol or rosaprostol;a diuretic; a sedating or non-sedating antihistamine; anticancer agentssuch as angiostatin and endostatin; anti-Alzheimers such as Doepezil andTacrine hydrochloride; and TNF alpha inhibitors such as Etanercept.

These cyclooxygenase inhibitors can further be used in combination withnitric oxide inhibitors disclosed in WO 96/28145.

Also, the invention encompasses pharmaceutical compositions for treatingCOX-2 mediated diseases as defined above comprising a non-toxictherapeutically effective amount of the compound of formula I and one ormore anti-ulcer agent and/or prostaglandins, which are disclosed in WO97/11701.

The useful prostaglandins include misoprostol, plus-minus methyl 11α,16-dihydroxy-16-methyl-9-oxoprost 13E-en-1-oate; enisoprost andmethyl-7-[2B-[6-(1-cyclopenten-1-yl)-4-hydroxy-4-methyl-1E,5E-hexadienyl]-3cc-hydroxy-5-oxo 1R, 1α-cyclopentyl]-4Z-heptenoate.Prostaglandins within the scope of the invention also includearbaprostil, enprostil, rioprostol, nocloprost, mexiprostil, omoprostol,dimoxaprost, tiprostanide and rosaprostol.

The present compounds may also be used in co-therapies, partially orcompletely, in place of other conventional antiinflammatories, such astogether with steroids, 5-lipoxygenase inhibitors, LTB₄ antagonists andLTA₄ hydrolase inhibitor's.

An example of LTB₄ is disclosed in WO97/29774. Suitable LTB₄ inhibitorsinclude, among others, ebselen, Bayer Bay-x-1005, Ciba Geigy compoundCGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Onocompound ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024,264086 and 292728, Ono compound ONO-LB457, Searle compound SC-S3228,calcitrol, Lilly compounds LY-210073, LY223982, LY233469, and LY255283,Ono compound ONO-LB-448, Searle compounds SC-41930, SC-50605 andSC-51146, and SK&F compound SKF-104493. Preferably, the LTB₄ inhibitorsare selected from ebselen, Bayer Bay-x-1005, Ciba Geigy compoundCGS-25019C, Leo Denmark compound ETH-61S, Lilly compound LY-293111, Onocompound ONO-4057 and Terumo compound TMK-688.

An example of 5-LO inhibitors is disclosed in WO97/29776. Suitable 5-LOinhibitors include, among others, masoprocol, tenidap, zileuton,pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadremphosphate and bunaprolast.

An example of LTA₄ hydrolase inhibitors is disclosed in WO97/29774.Suitable LTA₄ hydrolase inhibitors include, among others, Rhone-PoulencRorer RP-64966.

The administration of the present invention may be for either preventionor treatment purposes. The methods and compositions used herein may beused alone or in conjunction with additional therapies known to thoseskilled in the art in the prevention or treatment of angiogenesis.Alternatively, the methods and compositions described herein may be usedas adjunct therapy. By way of example, the cyclooxygenase-2 inhibitormay be administered alone or in conjunction with other antineoplasticagents or other growth inhibiting agents or other drugs or nutrients.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which couldbe selected for treatment of angiogenesis by combination drugchemotherapy. Such antineoplastic agents fall into several majorcategories, namely, antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and a category of miscellaneous agents.Alternatively, other anti-neoplalstic agents, such as metallomatrixproteases inhibitors (MMP), such as MMP-13 inhibitors includingbatiastat, marimastat. Agouron Pharmaceuticals AG-3340, and RocheRQ-32-3555, or alpha,beta,inhibitors may be used.

A first family of antineoplastic agents which may be used in combinationwith a selective cyclooxygenase-2 inhibitor consists ofantimetabolite-type antineoplastic agents. Suitable antimetaboliteantineoplastic agents may be selected from the group consisting of5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium,carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabinephosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FQ-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES. norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT anduricytin.

A second family of antineoplastic agents which may be used incombination with a selective cyclooxygenase-2 inhibitor consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from the group consisting ofShionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone,Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine,diplatinum cytostatic. Erba distamycin derivatives, Chugai DWA-2114R,ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium,fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide,iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121,NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine,Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, YakultHonsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine,temozolomide, teroxirone, tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith a selective cyclooxygenase-2 inhibitor consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from the group consisting of Taiho 4181-A, aclarubicin,actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative,Ajinomoto AN-201-II. Ajinomoto AN-3, Nippon Soda anisomycins,anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859,Bristol-Myers BMY-25067. Bristol-Myers BMY-25551, Bristol-MyersBMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B,Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b.Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin,mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, NipponKayaku NKT-OI, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-2S024 andzorubicin.

A fourth family of antineoplastic agents which may be used incombination with the selective cyclooxygenase-2 inhibitor consists of amiscellaneous family of antineoplastic agents selected from the groupconsisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile.amsacrine, Angiostat, ankinomycin, anti-neoplaston AIO, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristo-Myers BMY-40481, Vestar boron-1O, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-1OO,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate,Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, FujisawaFR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178,grifolan NMF-5N, hexadecylphosphocholine, Green Cross H0-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine,isotretinoin. Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-LambertPD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1OO1, ICRT peptideD, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin,probimane, procarbazine, proglumide, Invitron protease nexin I, TobishiRA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine,retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976,SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharmSP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed,SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237,Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680,taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29,tocotrienol, Topostin, Teijin TT-82, kyowa Hakko UCN-O1, Kyowa HakkoUCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate,vincristine, vindesine, vinestramide, vinorelbine, vintriptol,vinzolidine, withanolides and Yamanouchi YM-534.

Examples of radioprotective agents which may be used in the combinationchemotherapy of this invention are AD-5, adchnon, amifostine analogues,detox, dimesna, 1-102, MN-159, N-acylated-dehydroalanines,TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofentransdermal, nabumetone, superoxide dismutase (Chiron) and superoxidedisrrtutase Enzon.

Methods for preparation of the antineoplastic agents described above maybe found in the literature. Methods for preparation of doxorubicin, forexample, are described in U.S. Pat. No. 3,590,028 and U.S. Pat. No.4,012,448. Methods for preparing metallomatrix protease inhibitors aredescribed in EP 780386, WO97/20824. WO96/15096. Methods for preparingSOD mimics are described in EP 524,101. Methods for preparingalpha,beta, inhibitors are described in W097/08174.

In addition, the selective COX-2 inhibitor may be administered inconjunction with other antiinflammatory agents for maximum safety andefficacy, including NSAID's, selective COX-1 inhibitors and inhibitorsof the leukotriene pathway, including 5-lipoxygenase inhibitors.Examples of NSAID's include indomethacin, naproxen, ibruprofen,salicylic acid derivatives such as aspirin, diclofenac, ketorolac,piroxicam, meloxicam, mefenamic acid, sulindac, tolmetin sodium,zomepirac, fenoprofen, phenylbutazone, oxyphenbutazone, nimesulide,zaltoprofen and letodolac.

Methods of Assessing Biological Activities:

Activities of the compounds of the formula I of the present inventionmay be demonstrated by the following assays.

In vitro Assays:

Human Cell Based COX-1 Assay:

Human peripheral blood obtained from health volunteers is diluted to1/10 volume with 3.8% sodium citrate solution. The platelet-rich plasmaimmediately obtained is washed with 0.14M sodium chloride solutioncontaining 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. Platelets are thenwashed with platelet buffer (Hanks buffer (calcium free) containing 0.2%BSA and 20 mM Hepes buffer). Finally, the human washed platelets (HWP)are suspended in platelet buffer at the concentration of 2.85×108cells/ml and stored at room temperature until used. The HWP suspension(70 μl aliquots, final 2.0×107 cells/ml) is placed in a 96-well U bottomplate and 10 μl aliquots of 12.6 mM CaCl₂ is added. Platelets areincubated with A23187 (final 10 μM, Sigma) with a test compound (0.1-100μM) dissolved in DMSO (final concentration; less than 0.01%) at 37° C.for 15 minutes. The reaction is quenched by adding EDTA (final 7.7 mM),and TxB2 in the supernatant quantitated by using a radioimmunoassay kit(supplied by Amersham) according to the manufacture's procedure.

Human Cell Based COX-2 Assay:

The human sell based COX-2 assay is carried as previously reported byMoore et al., Inflam. Res., Vol. 45, pp. 54-, 1996. Confluent humanumbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well Ubottom plate are washed with 100 μl of RPMI1640 containing 2% FCS andincubation with hIL-1β (final concentration 300 U/ml, R & D Systems) at37° C. for 24 hours. After washing, the activated HUVECs are stimulatedwith A23187 (final concentration 30 μM) in Hanks buffer containing 0.2%BSA, 20 mM Hepes and a test compound (0.1 nM-100 μM) dissolved in DMSSO(final concentration; less than 0.01%) 37° C. for 15 minutes.6-Keto-PGF_(1α), stable metabolite of PGI₂, in the supernatant isquantitated after adequate dilution by using a radioimmunoassay kit(supplied by Amersham) according to the manufacture's procedures.

Canine In Vitro Assays

The following canine cell based COX 1 and COX-2 assays have beenreported in Ricketts et al., Evaluation of Selective Inhibition ofCanine Cyclooxygenase 1 and 2 by Carprofen and Other NonsteroidalAnti-inflammatory Drugs, American Journal of Veterinary Research, 59(11), 1441-1446.

Protocol for Evaluation of Canine COX-1 Activity

Test drug compounds were solubilized and diluted the day before theassay was to be conducted with 0.1 mL of DMSO/9.9 mL of Hank's balancedsalts solution (HBSS), and stored overnight at 4° C. On the day that theassay was carried out, citrated blood was drawn from a donor dog,centrifuged at 190×g for 25 min at room temperature, and the resultingplatelet-rich plasma was then transferred to a new tube for furtherprocedures. The platelets were washed by centrifuging at 1500×g for 10min at room temperature. The platelets were washed with platelet buffercomprising Hank's buffer (Ca free) with 0.2% bovine serum albumin (BSA)and 20 mM HEPES. The platelet samples were then adjusted to 1.5×10⁷/mL,after which 50 μl of calcium ionophore (A23187) together with a calciumchloride solution were added to 50 μl of test drug compound dilution inplates to produce final concentrations of 1.7 μM A23187 and 1.26 mM Ca.Then, 100 μl of canine washed platelets were added and the samples wereincubated at 37° C. for 15 min, after which the reaction was stopped byadding 20 μl of 77 mM EDTA. The plates were then centrifuged at 2000×gfor 10 min at 4° C., after which 50 μl of supernatant was assayed forthromboxane B₂ (TXB₂) by enzyme-immunoassay (EIA). The pg/mL of TXB₂ wascalculated from the standard line included on each plate, from which itwas possible to calculate the percent inhibition of COX-1 and the IC₅₀values for the test drug compounds.

Protocol for Evaluation of Canine COX-2 Activity

A canine histocytoma (macrophage-like) cell line from the American TypeCulture Collection designated as DH82, was used in setting up theprotocol for evaluating the COX-2 inhibition activity of various testdrug compounds. There was added to flasks of these cells 10 μg/mL ofLPS, after which the flask cultures were incubated overnight. The sametest drug compound dilutions as described above for the COX-1 protocolwere used for the COX-2 assay and were prepared the day before the assaywas carried out. The cells were harvested from the culture flasks byscraping, and were then washed with minimal Eagle's media (MEM) combinedwith 1% fetal bovine serum, centrifuged at 1500 rpm for 2 min, andadjusted to a concentration of 3.2×10⁵ cells/mL. To 50 μl of test drugdilution there was added 50 μl of arachidonic acid in MEM to give a 10μM final concentration, and there was added as well 100 μl of cellsuspension to give a final concentration of 1.6×10⁵ cells/mL. The testsample suspensions were incubated for 1 hr and then centrifuged at 1000rpm for 10 min at 4° C., after which 50 μl aliquots of each test drugsample were delivered to EIA plates. The EIA was performed forprostaglandin E₂ (PGE₂), and the pg/mL concentration of PGE₂ wascalculated from the standard line included on each plate. From this datait was possible to calculate the percent inhibition of COX-2 and theIC₅₀ values for the test drug compounds. Repeated investigations ofCOX-1 and COX-2 inhibition were conducted over the course of severalmonths. The results are averaged, and a single COX-1:COX-2 ratio iscalculated.

Whole blood assays for COX-1 and COX-2 are known in the art such as themethods described in C. Brideau, et al., A Human Whole Blood Assay forClinical Evaluation of Biochemical Efficacy of CyclooxygenaseInhibitors, Inflammation Research, 45, 68-74, (1996). These methods maybe applied with feline, canine or human blood as needed.

In Vivo Assays:

Canine Whole Blood ex Vivo Determinations of COX-1 and COX-2 ActivityInhibition

The in vivo inhibitory potency of a test compound against COX-1 andCOX-2 activity may be evaluated using an ex vivo procedure on caninewhole blood. Three dogs were dosed with 5 mg/kg of the test compoundadministered by oral gavage in 0.5% methylcellulose vehicle and threedogs were untreated. A zero-hour blood sample was collected from alldogs in the study prior to dosing, followed by 2- and 8-hour post-doseblood sample collections. Test tubes were prepared containing 2 μL ofeither (A) calcium ionophore A23187 giving a 50 μM final concentration,which stimulates the production of thromboxane B₂ (TXB₂) for COX-1activity determination; or of (B) lipopolysaccharide (LPS) to give a 10μg/mL final concentration, which stimulates the production ofprostaglandin E₂ (PGE₂) for COX-2 activity determination. Test tubeswith unstimulated vehicle were used as controls. A 500 μL sample ofblood was added to each of the above-described test tubes, after whichthey were incubated at 37° C. for one hr in the case of the calciumionophore-containing test tubes, and overnight in the case of theLPS-containing test tubes. After incubation, 10 μL of EDTA was added togive a final concentration of 0.3%, in order to prevent coagulation ofthe plasma which sometimes occurs after thawing frozen plasma samples.The incubated samples were centrifuged at 4° C. and the resulting plasmasample of ˜200 μL was collected and stored at −20° C. in polypropylene96-well plates. In order to determine endpoints for this study, enzymeimmunoassay (EIA) kits available from Cayman were used to measureproduction of TXB₂ and PGE₂, utilizing the principle of competitivebinding of tracer to antibody and endpoint determination by colorimetry.Plasma samples were diluted to approximate the range of standard amountswhich would be supplied in a diagnostic or research tools kit, i.e.,1/500 for TXB₂ and 1/750 for PGE₂.

The data set out in Table 2 below show how the percent inhibition ofCOX-1 and COX-2 activity is calculated based on their zero hour values.The data is expressed as treatment group averages in pg/ml of TXB₂ andPGE₂ produced per sample. Plasma dilution was not factored in said datavalues.

The data in Table 2 show that, in this illustration, at the 5 mg/kg dosethere was significant COX-2 inhibition at both timepoints. The data inTable 2 also show that at the 5 mg/kg dose there was no significantinhibition of COX-1 activity at the timepoints involved. Accordingly,the data in Table 2 clearly demonstrates that at the 5 mg/kg dosageconcentration this compound possesses good COX-2 selectivity.

TABLE 2 COX-1 ACTIVITY INHIBITION — Group Averages TXB₂ Pg/mL/WellPercent Inhibition Hour 0-hour 2-hour 8-hour 2-hour 8-hour Untreated 4645 140 2% 0% 5 mg/kg 41 38 104 7% 0% COX-2 ACTIVITY INHIBITION — GroupAverages PGE₂ Pg/mL/Well Percent Inhibition Hour 0-hour 2-hour 8-hour2-hour 8-hour Untreated 420 486 501 0% 0% 5 mg/kg 711 165 350 77% 51%

COX inhibition is observed when the measured percent inhibition isgreater than that measured for untreated controls. The percentinhibition in the above table is calculated in a straightforward mannerin accordance with the following equation:

(PGE₂ at t=0)−(PGE₂ at t=2)% Inhibition (2-hour)= (PGE₂ at t=0)

Carrageenan Induced Foot Edema in Rats

Male Sprague-Dawley rats (5 weeks old, Charles River Japan) are fastedovernight. A line is drawn using a marker above the ankle on the righthind paw and the paw volume (V0) is measured by water displacement usinga plethysmometer (Murromachi). Animals are given orally either vehicle(0.1% methyl cellulose or 5% Tween 80) or a test compound (2.5 ml per100 g body weight). One hour later, the animals are then injectedintradermally with λ-carrageenan (0.1 ml of 1% w/v suspension in saline,Zushikagaku) into right hind paw (Winter et al., Proc. Soc. Exp. Biol.Med., Vol. 111, p. 544-, 1962; Lombaridino et al., Arzneim. Forsch.,Vol. 25, p. 1629-, 1975) and three hours later, the paw volume (V3) ismeasured and the increase in volume (V3-V0) calculated. Since maximuminhibition attainable with classical NSAIDs is 60-70%, ED₃₀ values arecalculated.

Gastric Ulceration in Rats

The gastric ulcerogenicity of a test compound is assessed by amodification of the conventional method (Ezer et al., J. Pharm.Pharmacol., Vol. 28, p. 655-, 1976; Cashin et al, J. Pharm. Pharmacol.,Vol. 29, pp. 330-336, 1977). Male Sprague-Dawley rats (5 weeks old,Chales River Japan), fated overnight, were given orally either vehicle(0.1% methyl cellulose or 5% Tween 80) or a test compound (1 ml per 100g body weight). Six hours after, the animals are sacrificed by cervicaldislocation. The stomachs are removed, inflated with 1% formalinsolution (10 ml), opened by cutting along the grater curvature. From thenumber of rats that show at least gastric ulcer or haemorrhaging erosion(including ecchymosis), the incidence ulceration is calculated. Animalsdo not have access to either food or water during the experiment.

Data Analysis:

Statistical program packages, SYSTANT (SYSTANT, INC.) and StatView(Abacus Cencepts, Inc.) for Macintosh are used. Difference between testcompound treated groups and control group are tested for using ANOVA.The IC₅₀ (ED₃₀) values are calculated from the equation for thelog-linear regression of concentration (dose) versus percent inhibition.

Most compounds prepared in the Working Examples as described hereinafterwere tested by at least one of the methods described above, and showedIC₅₀ values of 0.001 μM to 3 μM with respect to inhibition of COX-2 ineither the canine or human assays.

The following examples contain detailed descriptions of the methods ofthe preparation of compounds of formula I. These detailed descriptionsfall within the scope of the invention and serve to exemplify the abovedescribed general synthetic procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended to restrict the scope of the present invention.

EXAMPLES AND PREPARATIONS

The invention is illustrated in the following non-limiting examples inwhich, unless stated otherwise: all operations were carried out at roomor ambient temperature, that is, in the range of 18-25° C.; evaporationof solvent was carried out using a rotary evaporator under reducedpressure with a bath of up to 60° C.; reactions were monitored by thinlayer chromatography (tic) and reaction times are given for illustrationonly; melting points (m.p.) given are uncorrected (polymorphism mayresult in different melting points); structure and purity of allisolated compounds were assured by at least one of the followingtechniques: tlc (Merck silica gel 60 F-254 precoated plates), massspectrometry, nuclear magnetic resonance (NMR) or infrared spectroscopy(IR). IR data were obtained on a FTIR 8200 (SHIMAZU Spectrometer).Yields are given for illustrative purposes only. Flash columnchromatography was carried out using Merck silica gel 60 (230-400 meshASTM). Low-resolution mass spectral data (EI) were obtained on aAutomass 120 (JEOL) mass spectrometer. Liquid Chromatography data wascollected on a Hewlett Packard 1100 Liquid Chromatography/Mass SelectiveDetector (LC/MSD). Analysis was performed on a Luna C-18 column withdimensions of 3.0×150 mm. The flow rate was 0.425 ml/min running agradient of 50% 0.1% aqueous formic acid and 50% acetonitrile to 100%acetonitrile in 15 minutes. The ionization type for the mass detector ofthe Mass Spectrophotometer was atmospheric pressure electrospray in thepositive ion mode with a fragmentor voltage of 50 volts. NMR data wasdetermined at 270 MHz (JEOL JNM-LA 270 spectrometer) using deuteratedchloroform (99.8% D), methanol (99.8% D) or dimethylsulfoxide (99.9% D)as solvent unless indicated otherwise, relative to tetramethylsilane(TMS) as internal standard in parts per million (ppm); conventionalabbreviations used are: s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, br=broad, etc.

The following abbrevation are used:

THF: tetrahydrofuran CH₂Cl₂: dichloromethane NaHCO₃: sodium bicarbonateHCl: hydrogen chloride MgSO₄: magnesium sulfate Na₂SO₄: sodium sulfateDME: dimethoxyethane n-BuLi: n-butyllithium DMF: dimethylformamide

Example 16-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-pyrdinesulfonamide

6-Hydrazino-3-pyridinesulfonamide Dihydrochloride. (Step 1)

To a solution of 6-chloro-3-pyridinesulfonamide (0.64 g, 3.32 mmol) inethanol (20 mL) was added hydrazine anhydrous (0.128 g, 3.99 mmol).After the reaction mixture was heated at reflux temperature for 5 hours,the solvent was removed. The residue was washed with methylene chlorideto give the subtitle compound (0.494 g, 79.0% yield).

¹H-NMR (DMSO-d₆) δ: 8.33 (d, J=2 Hz, 1H), 8.26 (brs, 1H), 7.75 (dd, J=2,9 Hz, 1H), 7.12-7.07 (brs, 2H), 6.76 (d, J=9 Hz, 1H), 4.34 (brs, 2H).

The solid (0.49 g, 2.6 mmol) was dissolved in 10% methanolic HCl (3 mL),and volatiles were removed by evaporation. The residue wasrecrystallized from methylene chloride-ether to give the subtitlecompound (0.574 g, 84.5% yield)

4,4,4-Trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione. (Step 2)

To a stirred solution of4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione (1 g, 3.39 mmol,J.Med.Chem., 1997, 40, 1347) in DME.(40 mL) was added furan-2-boronicacid (0.455 g, 4.07 mmol), bis(triphenylphosphine) palladium(.)chloride(0.271 g, 0.386 mmol) and saturated NaHCO3 solution (12 mL) at roomtemperature under nitrogen. The mixture was heated at reflux temperaturefor 5 hours, and cooled down to room temperature. The reaction mixturewas filtered through celite, the filtrate was poured into water and thewhole was extracted with ethyl acetate (30 mL×3). The organic layer waswashed with brine, dried over sodium sulfate, and concentrated in vacuo.The residue was purified by flash chromatography eluting withhexane/ethyl acetate (3/1) to give the subtitle compound (0.586 g, 61.2%yield). MS (EI): m/z 282 (M⁺).

[5-[4-(2-Furyl)phenyl]-1-[2-(5-sulfamoyl)pyridyl]-3-trifluoromethyl-1H-pyrazole.(Step 3)

A mixture of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione(0.282 g, 1 mmol) and 6-hydrazino-3-pyridinesulfonamide dihydrochloride(0.287 g, 1.1 mmol) in ethanol (10 mL) was heated at reflux temperaturefor 18 hours. The reaction mixture was cooled and the solvent removedunder reduced pressure. The residue was redissolved in ethyl acetate (30mL) and washed with saturated aqueous NaHCO3 (20 mL), brine. The organiclayer was dried over sodium sulfate, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica eluting withhexane/ethyl acetate (3/1). The resulting solid was recrystallized fromdichloromethane/hexane to give the title compound (0.05 g, 11.5% yield).

mp: 157.2° C. ¹H-NMR (CDCl₃) δ: 8.79 (d, J=2 Hz, 1H), 8.31 (dd, J=3, 9Hz, 1H), 7.91 (d, J=9 Hz, 1H), 7.68 (d, J=8 Hz, 2H), 7.51 (d, J=2 Hz,2H), 7.30 (d, J=8 Hz, 2H), 6.79 (s, 1H), 6.73 (d, J=4 Hz, 1H), 6.51 (dd,J=2, 4 Hz, 1H), 5.00 (brs, 2H). Anal.Calcd.for.C₁₉H₁₃F₃N₄O₃S, 0.2H₂O: C,52.10; H, 3.08; N, 12.79. Found: C, 52.01; H, 3.19; N, 12.44. MS (EI):m/z 434 (M⁺).

Example 25-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide

5-Hydrazino-2-pyridinesulfonamide Hydrochloride (Step 1)

To a suspension of 5-amino-2-pyridinesulfonamide (7.0 g, 0.040 mol, C.Komfeld, J. Amer. Chem. Soc. 1695 (1942)) in conc HCl (60 mL) and H₂O(20 mL), sodium nitrite (3.6 g, 0.052 mol) in H₂O (50 mL) was addeddropwise at 0° C. and the mixture was stirred for 30 min. The mixturechanged to yellow brown solution and tin(II) chloride dihydrate (36 g,0.16 mol) in conc HCl (30 mL) was added dropwise below 5° C. and stirredfor 1 hour at 0° C. The mixture was made basic by addition of aqueousNaOH (pH=8). The resultant suspension was added THF (400 mL) and stirredfor 10 min. The white precipitate was separated by celite filtration andwashed with THF (100 mL×3). The filtrate was separated in two phase andorganic phase was separated. Water phase was extracted with THF (150mL×2), dried (MgSO₄), and concentrated in vacuo gave brown oil. The oilwas disolved in 10% HCl-MeOH (50 mL) and concentrated in vacuo gavebrown amorphous solid. Crystallization from CH₂Cl₂ gave the titledcompound as a brown solid (5.0 g, 56%).

¹H-NMR (DMSO-d₆) δ: 10.74 (br s, 2H), 8.35 (d, J=2.3 Hz, 1H), 7.82 (d,J=8.6 Hz, 1H), 7.49 (dd, J=2.3, 8.6 Hz, 1H), 7.30 (br s, 1H).

5-[5-[4-(2-Furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 2)

The title compound was prepared according to the procedure of Example 1(step 2) using 5-hydrazino-2-pyridinesulfonamide hydrochloride insteadof 2-hydrazino-5-pyridine sulfonamide dihydrochloride.

mp: 140-170° C. ¹H-NMR (CDCl₃) δ: 8.69 (d, J=2.3 Hz, 1H), 8.02 (d, J=8.6Hz, 1H), 7.90 (dd, J=2.3, 8.6 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.51 (d,J=1.6 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 6.84 (s, 1H), 6.75 (d, J=3.5 Hz,1H), 6.51 (dd, J=2.0, 3.5 Hz, 1H), 5.07 (br 2H). Anal. Calcd. forC₁₉H₁₃N₄O₃F₃S: C, 52.53; H, 3.02; N, 12.90. Found: C, 52.43; H, 3.03; N,12.66.

Example 35-[5-[3-Chloro-4-(1,3-oxazol-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide

4-Bromo-2-chloro-N-(2,2-diethoxyethyl)benzamide (Step 1).

To a suspension of 2-chloro-4-bromobenzoic acid (10.0 g, 42.47 mmol) inCH2Cl2 (1000 mL) was added aminoacetaldehyde diethyl acetal (5.1 mL,46.72 mmol) and WSC (9.77 g, 50.96 mmol) at room temperature, andstirred for 4 hours. The mixture was washed with water (100 mL), driedover MgSO₄. Removal of the solvent, gave title compound (14.88 g, 100%yield).

¹H-NMR (CDCl₃) δ 7.56-7.59 (m, 2H), 7.47 (dd, J=1.8, 8.2 Hz, 2H), 6.51(br s, 1H), 4.64 (t, J=5.4 Hz, 1H), 3.53-3.80 (m, 6H), 1.23 (t, J=6.9Hz, 3H).

4-Bromo-2-chloro-N-(2-oxoethyl)benzamide (Step 2).

To a solution of 4-bromo-2-chloro-N-(2,2-diethoxyethyl)benzamide (14.88g, 42.44 mmol) in THF (50 mL) was added 2N HCl (50 mL) at roomtemperature. After 24 hours, water (100 mL) was added to the mixture,then the mixture was extracted with ethyl acetate (100 mL×2), theorganic layer was washed with water (50 mL), dried over MgSO4. Removalof the solvent, gave a title compound (6.98 g, 60% yield).

¹H-NMR (CDCl₃) δ 9.77 (s, 1H), 7.61-7.65 (m, 2H), 7.47-7.51 (m, 1H),7.07 (br s, 1H), 4.43-4.45 (m, 2H).

2-(4-Bromo-2-chlorophenyl)-1,3-oxazole (Step 3).

To a stirred solution of 4-bromo-2-chloro-N-(2-oxoethyl)benzamide (1.00g, 3.617 mmol) in CH2Cl2 (30 mL) were added triphenylphosphine (1.90 g,7.234 mmol), iodine (1.84 g, 7.234 mmol) and triethylamine (2.0 mL,14.47 mmol) at room temperature. After 24 hour, the mixture was washedwith water (20 mL), dried over MgSO4. Removal of the solvent, gave anoily recidue, which was purified by flash chromatography eluting withethyl acetate/hexane (1/5) to give title compound (0.185 g, 20% yield).

¹H-NMR (CDCl₃) δ 7.88 (d, J=8.4 Hz, 1H), 7.80 (d, J=0.8 Hz, 2H), 7.70(d, J=1.6 Hz, 1H), 7.51 (dd, J=2.0, 8.4 Hz, 1H), 7.32 (d, J=0.7 Hz, 2H).

1-[3-Chloro-4-(1,3-oxazol-2-yl)phenyl]-1-ethanone (Step 4).

To a stirred solution of 2-(4-bromo-2-chlorophenyl)-1,3-oxazole (2.88 g,11.14 mmol) in 1,4-dioxane (70 mL) were addedtributhyl(1-ethoxyvinyl)tin (4.5 mL, 13.37 mmol), LiCl (1.18 g, 27.85mmol) and tetrakis(triphenylphosphine)palladium(0) (1.28 g, 1.11 mmol)at room temperature under nitrogen. The mixture was heated at refluxtemperature for 4 hours, and cooled down to room temperature, thesolvent was removed under reduced pressure and the residue was dissolvedin ethyl acetate (50 mL), washed with water (20 mL), dried over MgSO4and concentrated in vacuo. The residue was dissolved in THF (30 mL) then2N HCl (30 ml) was added at room temperature. After 2 hours, saturatedNaHCO3 (100 mL) was added to the mixture. The mixture was extracted withethyl acetate (300 mL) dried over MgSO4. Removal of the solvent, gave anoily residue, which was purified by flash chromatography eluting withethyl acetate/hexane (1/4) to give title compound (1.891 g, 77% yield).

¹H-NMR (CDCl₃) δ 8.15 (d, J=8.1 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.92(dd, J=1.8, 8.2 Hz, 1H), 7.84 (d, J=0.7 Hz, 1H), 7.38 (d, J=0.7 Hz, 1H),2.64 (s, 3H).

1-[3-Chloro-4-(1,3-oxazol-2-yl)phenyl]-4,4,4-trifluoro-1,3-butanedione(Step 5)

To a solution of 1-[3-chloro-4-(1,3-oxazol-2-yl)phenyl]-1-ethanone (1.89g, 8.572 mmol) in t-butyl methyl ether (100 mL) were added ethyltrifluoroacetate (1.1 mL, 9.38 mmol) and 28%wt sodium methoxide in MeOH(2.6 ml) at 0° C. and stirred at room temperature for 4 hours. Water(100 mL) was added to the mixture, the mixture was neutralized with 2NHCl, extracted with ethyl acetate (100 mL×2) and dried over MgSO4.Removal of the solvent, gave a title compound (3.08 g).

5-[5-[3-Chloro-4-(1,3-oxazol-2-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 6)

The subtitle compound was prepared according to the procedure of Example1 (Step 2) using1-[3-chloro-4-(1,3-oxazol-2-yl)phenyl]-4,4,4-trifluoro-1,3-butanedione,instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione and5-hydrazino-2-pyridinesulfonamide hydrochloride instead of2-hydrazino-5-sulfamoylpyridine dihydrochloride.

mp: 156° C. ¹H-NMR (CDCl₃) δ: 8.69 (dd, J=0.8, 2.5 Hz, 1H), 8.08 (d,J=0.8 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.92 (dd, J=2.5, 8.4 Hz, 1H),7.84 (d, J=0.8 Hz, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.36 (d, J=0.8 Hz, 1H),7.16 (dd, J=1.8, 8.2 Hz, 1H), 6.92 (s, 1H), 5.14 (br s, 2H). Anal.Calcd. for C₁₈H₁₁ClF₃N₅O₃S.0.2H₂O: C, 45.67; H, 2.43; N, 14.79. Found:C, 46.01; H, 2.59; N, 14.48.

Example 45-{4-Chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamideHydrochloride

5-[5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 1).

A mixture of 1-(4-bromophenyl)-4,4,4-trifluoro-1,3-butanedione (preparedaccording to the method of J.Med.Chem., 1997, 40, 1347. 1.09 g, 3.71mmol) and 5-hydrazino-2-pyridinesulfonamide hydrochloride (1.00 g, 4.45mmol) in ethanol (50 ml) was refluxed for 18 hr. After evaporation, theobtained residue was chromatographed on a column of silica gel (200 g)eluting with ethyl acetate/hexane (1:2) to afford 1.44 g (87%) of thetitle compound as a white solid.

¹H-NMR (DMSO-d6) δ: 8.71 (1H, d, J=2.3 Hz), 8.08 (1H, dd, J=2.3 and 8.4Hz), 8.02 (1H, d, J=8.4 Hz), 7.70-7.64 (2H, m), 7.63 (2H, br s),7.37-7.31 (2H, m), 7.36 (1H, s).

5-[5-(4-Bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 2)

To a solution of5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(350 mg, 0.783 mmol) in N,N-dimethylformamide (12 ml) was addedN-chlorosuccinimide (1.05 g, 7.83 mmol) at room temperature. After themixture was stirred for 18 hr, 1.05 g of N-chlorosuccinimide was added.The resulting mixture was stirred for further 36 hr. 20 ml of saturatedaqueous sodium thiosulfate and 50 ml of diethyl ether were added and thetwo-phase-mixture was stirred for 0.5 hr. The separated organic layerwas washed with water (20 ml×3) and dried over magnesium sulfate.Removal of solvent gave a pale yellow gum, which was chromatographed ona column of silica gel (50 g) eluting with ethyl acetate/hexane (1:3) toafford 236 mg (63%) of the title compound as a white solid.

¹H-NMR (CDCl₃) δ: 8.59 (1H, d, J=2.5 Hz), 8.03 (1H, d, J=8.4 Hz), 7.83(1H, dd, J=2.5 and 8.6 Hz), 7.67-7.61 (2H, m), 7.21-7.16 (2H, m), 5.11(2H, br s). MS (EI): 480 and 482 (M⁺).

5-{4-Chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide(Step 3)

A mixture of5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(236 mg, 0.489 mmol), 4-(tributylstannyl)-1,3-thiazole 238 mg, 0.636mmol), lithium chloride (27 mg, 0.636 mmol) andtetrakis(triphenyphosphine)palladium (57 mg, 0.0489 mmol) in 1,4-dioxane(10 ml) was refluxed for 5 hr under nitrogen atmosphere. Afterevaporation, the residue obtained was chromatographed on a column ofsilica gel (50 g) eluting with ethyl acetate/hexane (3:4) to afford 200mg (84%) of the title compound as a pale brown gum.

¹H-NMR (CDCl₃) δ: 8.89 (1H, d, J=2.0 Hz), 8.62 (1H, d, J=1.6 Hz),8.05-7.98 (2H, m), 7.94 (1H, dd, J=2.8 and 8.6 Hz), 7.83-7.76 (1H, m),7.65 (1H, d, J=2.0 Hz), 7.39-7.33 (2H, m), 5.55 (2H, br s).

5-[4-Chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamideHydrochloride (Step 4)

To a solution of5-{4-chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide(200 mg, 0.412 mmol) in dichloromethane (6 ml) was added methanolichydrochloric acid (2 ml) at room temperature. The solution stood for awhile and a formed solid was collected to give 160 mg (74%) of the titlecompound as a white solid.

m.p.: 157° C. (recrystallized from dichloromethane/methanol); ¹H-NMR(DMSO-d6) δ: 9.24 (1H, d, J=2.0 Hz), 8.70 (1H, d, J=2.3 Hz), 8.33 (1H,d, J=1.8 Hz), 8.16-8.08 (3H, m), 8.02 (1H, d, J=8.4 Hz), 7.62 (2H, brs), 7.56-7.50 (2H, m). MS (EI): 485 (M⁺).

Example 55-{5-[4-(1,3-Thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide

1-[4-Nitro-3-(trifluoromethyl)phenyl]-1-ethanone (Step 1)

A mixture of 4-bromo-1-nitro-2-(trifluoromethyl)benzene (1.87 g, 6.93mmol), tributyl(1-ethoxyvinyl)tin (3.00 g, 8.31 mmol), Pd(PPh₃)₄ (801mg, 0.693 mmol), and LiCl (734 mg, 17.3 mmol) in 1,4-dioxane (50 ml) washeated to reflux for 7 hours. The mixture was filtered through a pad ofCelite with ethyl acetate. The filtrate was washed with water (100 ml)and brine (100 ml), dried over MgSO₄, and evaporated in vacuo. To theobtained residue were added 2N HCl (20 ml) and THF (60 ml). The mixturewas stirred at room temperature for 1.5 hours. Saturated aqueous NaHCO₃(60 ml) was added and the aqueous layer was extracted with ethyl acetate(100 ml×2). The combined organic layer was dried over MgSO₄, andevaporated in vacuo. The resulting residue was chromatographed oversilica gel with hexane/ethyl acetate (3:1) to give 1.51 g (94%) of thetitle compound as a white solid.

¹H-NMR (CDCl₃) δ: 8.39 (1H, d, J=1.9 Hz), 8.28 (1H, dd, J=1.9, 8.4 Hz),7.96 (1H, d, J=8.4 Hz), 2.71 (3H, s).

1-[4-Amino-3-(trifluoromethyl)phenyl]-1-ethanone (Step 2)

A mixture of 1-[4-nitro-3-(trifluoromethyl)phenyl]-1-ethanone (1.41 g,6.05 mmol), Fe powder (1.69 g, 30.2 mmol), and NH₄Cl (324 mg, 6.05 mmol)in EtOH (24 ml) and water (9 ml) was heated to reflux for 2.5 hours.After cooling to room temperature, the mixture was filtered through apad of Celite and the filtrate was concentrated. And the residue wasdissolved with ethyl acetate (100 ml), washed with water (100 ml), driedover MgSO₄, and concentrated in vacuo to give 1.22 g (quant.) of thetitle compound as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 8.07 (1H, d, J=1.9 Hz), 7.92 (1H, dd, J=1.6, 8.4 Hz),6.75 (1H, d, J=8.4 Hz), 2.53 (3H, s).

1-[4-Bromo-3-(trifluoromethyl)phenyl]-1-ethanone (Step s3)

To a solution of t-butyl nitrite (936 mg, 9.08 mmol) and CuBr₂ (1.62 g,7.26 mmol) in MeCN (35 ml) was added a solution of1-[4-amino-3-(trifluoromethyl)phenyl]-1-ethanone (1.30 g, 6.40 mmol ) inMeCN (15 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes,poured into 2N HCl (100 ml), and extracted with ethyl acetate (100 ml).The organic layer was washed with 2N HCl (50 ml), dried over MgSO₄, andconcentrated in vacuo to give 1.34 g (78%) of the title compound as awhite solid.

¹H-NMR (CDCl₃) δ: 8.25 (1H, d, J=2.2 Hz), 7.95 (1H, dd, J=2.2, 8.4 Hz),7.84 (1H, d, J=8.4 Hz), 2.63 (3H, s).

1-[4-Bromo-3-(trifluoromethyl)phenyl]-4,4,4-trifluoro-1,3-butanedione(Step 4)

To a solution of 1-[4-bromo-3-(trifluoromethyl)phenyl]-1-ethanone (1.34g, 5.65 mmol) in THF (30 ml) was added lithium bis(trimethylsilyl)amide(1.0 M THF solution, 6.8 ml, 6.8 mmol) at −78° C. The mixture wasstirred at 0° C. for 15 minutes and the solution was again cooled to−78° C. N-trifluoroacetylimidazole (1.15 g, 6.78 mmol) was added to thesolution at the same temperature. The resulting mixture was stirred at−78° C. for 15 minutes and at room temperature for 2.5 hours. Thereaction was quenched with 2N HCl (100 ml). The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (100ml×2). The combined organic layer was washed with brine (200 ml), driedover MgSO₄, and concentrated in vacuo to give 1.80 g (88%) of the titlecompound as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 8.23 (1H, d, J=2.1 Hz), 7.93 (1H, dd, J=1.8, 8.4 Hz),7.89 (1H, d, J=8.4 Hz), 6.57 (1H, s).

5-{5-[4-Bromo-3-(trifuoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide(Step 5)

The title compound was prepared according to the procedure of step 1 inthe example 4 using1-[4-bromo-3-(trifluoromethyl)phenyl]-4,4,4-trifluoro-1,3-butanedione,instead of 1-(4-bromophenyl)-4,4,4-trifluoro-1,3-butanedione.

¹H-NMR (CDCl₃) δ: 8.64 (1H, d, J=2.6 Hz), 8.08 (1H, d, J=8.4 Hz), 7.91(1H, dd, J=2.6, 8.4 Hz), 7.76 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=2.0 Hz),7.15 (2H, dd, J=2.2, 8.3 Hz), 5.17 (2H, br).

5-{5-[4-(1,3-Thiazol-4-yl)-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide(Step 6)

The title compound was prepared according to the procedure of step 3, 4in the example 4 using5-{5-[4-bromo-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide,instead of5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.

m.p.: 114° C. (from ethanol/hexane); ¹H-NMR (DMSO-d₆) δ: 9.23 (1H, d,J=1.8 Hz), 8.80 (1H, d, J=2.4 Hz), 8.17 (1H, dd, J=2.4, 8.1 Hz), 8.05(1H, d, J=8.4 Hz), 7.98-7.94 (2H, m), 7.71 (1H, d, J=7.8 Hz), 7.67-7.62(3H, m), 7.56 (1H, s). MS; 519 (M⁺).

Example 65-{5-[4-(1,3-Thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamideHydrochloride

5-{5-[4-(1,3-Thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide(Step 1)

The title compound was prepared according to the procedure of step 3 inthe Example 4 using5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Example 4, step 1), instead of5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.

¹H-NMR (CDCl₃) δ: 8.89 (1H, d, J=1.8 Hz), 8.67 (1H, d, J=2.0 Hz),8.02-7.93 (3H, m), 7.87 (1H, dd, J=2.5 and 8.4 Hz), 7.63 (1H, d, J=2.0Hz), 7.34-7.28 (2H, m), 6.86 (1H, s), 5.43 (2H, br s).

5-{5-[4-(1,3-Thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamideHydrochloride (Step 2)

To a solution of5-{5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide(470 mg, 1.04 mmol) in dichloromethane (6 ml) was added methanolichydrochloric acid (4 ml) at room temperature. After evaporation, theresidue obtained was recrystallized from methanol/diethyl ether to give467 mg (92%) of the title compound as a white solid.

m.p.: 121° C. (recrystallized from methanol/diethyl ether); ¹H-NMR(DMSO-d6) δ: 9.23 (1H, d, J=1.8 Hz), 8.74 (1H, d, J=2.3 Hz), 8.31 (1H,d, J=2.0 Hz), 8.11 (1H, dd, J=2.5 and 8.4 Hz), 8.08-8.00 (3H, m), 7.63(2H, br s), 7.50-7.43 (2H, m), 7.38 (1H, s). MS (EI): 451 (M⁺).

Example 75-{5-Ethyl-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamideHydrochloride

4-Bromo-N-methoxy-N-methylbenzamide (Step 1)

To a solution of 4-bromobenzoyl chloride (12.43 g, 56.6 mmol) andN,O-dimethyl hydroxyamine hydrochloride (8.29 g, 85.0 mmol) in CH₂Cl₂(200 ml) was added triethylamine (23.7 ml, 170 mmol) at 0° C. Themixture was stirred at room temperature for 2 hours. Water (200 ml) wasadded and the aqueous layer was extracted with CH₂Cl₂ (150 ml×2). Thecombined organic layer was washed with 2N HCl (200 ml), saturatedaqueous NaHCO₃ (200 ml), and brine (200 ml), dried over Na₂SO₄, andconcentarated in vacuo to give 14.9 g (quant.) of the title compound asa white solid.

¹H-NMR (CDCl₃) δ: 7.61-7.52 (4H, m), 3.54 (3H, s), 3.36 (3H, s).

1-(4-Bromophenyl)-1-butanone (Step 2)

To a solution of 4-bromo-N-methoxy-N-methylbenzamide (13.4 g, 54.2 mmol)in THF (200 ml) was added n-PrMgBr (2M THF solution, 54.0 ml, 108 mmol)at 0° C. The mixture was stirred at room temperature for 45 minutes.Further n-PrMgBr (13.5 ml, 27.0 mmol) was added at 0° C., and themixture was stirred at room temperature for 30 minutes. The excessreagent was quenched with saturated aqueous NH₄Cl (200 ml), and ether(300 ml) was added. The organic layer was separated and the aqueouslayer was extracted with ether (300 ml). The combined organic layer waswashed with water (200 ml) and brine (200 ml), dried over Na₂SO₄, andconcentrated in vacuo. The obtained residue was chromatographed on acolumn of silica gel eluting with hexane/ethyl acetate (15:1) to give10.1 g (82%) of the title compound as a yellow solid.

¹H-NMR (CDCl₃) δ: 7.82 (2H, d, J=8.6 Hz), 7.60 (2H, d, J=8.6 Hz), 2.91(2H, t, J=7.2 Hz), 1.76 (2H, sextet, J=7.3 Hz), 1.00 (3H, t, J=7.4 Hz).

1-(4-Bromophenyl)-2-ethyl-4,4,4-trifluoro-1,3-butanedione (Step 3)

To a solution of hexamethyldisilazane (4.92 g, 30.5 mmol) in THF (10 ml)was added dropwise n-BuLi (1.57 M hexane solution, 19.4 ml, 30.5 mmol)at −78° C. and the mixture was stirred at room temperature for 15minutes. The mixture was cooled down to −78° C. again and1-(4-bromophenyl)-1-butanone (5.77 g, 25.4 mmol) in THF (25 ml) wasadded dropwise over 15 min. The resulting mixture was stirred at −78° C.for 30 minutes, then allowed to warm up to 0° C. and stirred for 40minutes. The solution was recooled down to −78° C. andN-trifluoroacetylimidazole (5.00 g, 30.5 mmol) was added. The mixturewas stirred at −78° C. for 20 minutes, and at room temperature for 2hours. The reaction was quenched with 2N HCl (30 ml). The organic layerwas separated and the aqueous layer was extracted with ethyl acetate (50ml×2). The combined organic layer was washed with brine (50 ml), driedover Na₂SO₄, and concentrated in vacuo. The residue was chromatographedover silica gel with hexane/ethyl acetate (8:1 to 3:1) to give 5.64 g(69%) of the title compound as a oil.

TLC: Rf=0.35 (hexane/ethyl acetate=5/1).

5-[5-(4-Bromophenyl)-4-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 4)

The title compound was prepared according to the procedure of step 1 inthe Example 4 using1-(4-bromophenyl)-2-ethyl-4,4,4-trifluoro-1,3-butanedione, instead of1-(4-bromophenyl)-4,4,4-trifluoro-1,3-butanedione.

¹H-NMR (CDCl₃) δ: 8.57 (1H, d, J=2.5 Hz), 7.94 (1H, d, J=8.4 Hz), 7.76(1 H, dd, J=2.5 and 8.4 Hz), 7.65-7.58 (2H, m), 7.15-7.08 (2H, m), 2.55(2H, q, Hz), 1.13 (3H, t, J=7.6 Hz).

5-{4-Ethyl-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide(Step 5)

The title compound was prepared according to the procedure of step 3 inthe Example 4 using5-[5-(4-bromophenyl)-4-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide,instead of5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.

¹H-NMR (CDCl₃) δ: 8.91 (1H, d, J=2.0 Hz), 8.60 (1H, d, J=2.5 Hz),8.07-8.00 (2H, m), 7.92 (1H, d, J=8.6 Hz), 7.80 (1H, dd, J=2.5 and 8.6Hz), 7.65 (1H, d, J=2.0 Hz), 7.34-7.27 (2H, m), 5.26 (2H, br s), 2.60(2H, q, J=7.7 Hz), 1.15 (3H, t, J=7.4 Hz).

5-{4-Ethyl-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamideHydrochloride (Step 6)

The title compound was prepared according to the procedure of step 2 inthe Example 6 using5-{4-ethyl-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide,instead of5-{5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide.

m.p.: 141° C. (recrystallized from dichloromethane/ethyl acetate);¹H-NMR (DMSO-d6) δ: 9.24 (1H, d, J=1.8 Hz), 8.61 (1H, d, J=2.5 Hz), 8.32(1H, d, J=1.8 Hz), 8.13-8.07 (2H, m), 8.02 (1H, dd, J=2.5 and 8.4 Hz),7.96 (1H, d, J=8.4 Hz), 7.56 (2H, br s), 7.50-7.45 (2H, m), 2.56 (2H, q,J=7.3 Hz), 1.10 (3H, t, J=7.4 Hz). MS (EI): 479 (M⁺).

Example 85-[4-Ethyl-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamideHydrochloride

5-[4-Ethyl-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 1).

The title compound was prepared according to the procedure of Example 7step 5 using 5-tributylstannylthiazole, instead of4-tributylstannylthiazole.

¹H-NMR (CDCl₃) δ: 8.83 (s, 1H), 8.59 (d, J=1.8 Hz, 1H), 8.17 (s, 1H),7.98 (d, J=7.7 Hz, 1H), 7.85 (dd, J=2.5, 8.4 Hz, 1H), 7.69 (d, J=8.6 Hz,2H), 7.28 (d, J=9.2 Hz, 2H), 5.07 (br s, 2H), 2.60 (q, J=7.4 Hz, 2H),1.16 (t, J=7.4 Hz, 3H).

5-[4-Ethyl-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamideHydrochloride (Step 2).

The title compound was prepared according to the procedure of Example 4step 4 using5-[4-ethyl-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide,instead of5-{4-chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide.

mp: 169° C. ¹H-NMR (DMSO-d6) δ: 9.15 (s, 1H), 8.63 (dd, J=0.8, 2.3 Hz,1H), 8.44 (d, J=0.7 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.98 (d, J=0.8 Hz,1H), 7.83 (d, J=8.6 Hz, 2H), 7.58 (br s, 2H), 7.48 (d, J=8.4 Hz, 2H),7.39 (s, 1H). Anal. Calcd. for C₂₀H₁₆F₃N₅O₂S₂.1HCl.1.5H₂O: C, 44.24; H,3.71; N, 12.90. Found: C, 44.54; H, 3.58; N, 12.83.

Example 95-{4-Fluoro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamideHydrochloride

1-(4-Bromophenyl)-2-fluoro-1-ethanone (Step 1)

A mixture of 2-bromo-1-(4-bromophenyl)-1-ethanone (8.54 g, 30.7 mmol),potassium fluoride (8.92 g, 153 mmol) and 18-crown-6 ether (4.06 g, 15.3mmol) in acetonitrile (170 ml) was refluxed for 7 hr. After evaporation,the mixture was dissolved in ethyl acetate (300 ml), washed with water(100 ml×2), and dried over magnesium sulfate. Removal of solvent gave6.8 g of brown solid, which was chromatographed on a column of silicagel (600 g) eluting with ethyl acetate/hexane (1:10) to afford 5.00 g(75%) of the title compound as a pale yellow solid.

¹H-NMR (CDCl₃) δ: 7.81-7.76 (2H, m), 7.68-7.63 (2H, m), 5.47 (2H, d,J=46.9 Hz).

5-[4-Fluoro-5-(4-bromopheny)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 2)

To a solution of 1-(4-bromophenyl)-2-fluoro-1-ethanone (3.54 g, 16.3mmol) in tetrahydrofuran (50 ml) was added dropwise 1M lithiumhexamethyldisilazide tetrahydrofuran solution (19.6 ml, 19.6 mmol) at−78° C. After stirring for 45 min., N-trifluoroacetylimidazole (2.3 ml,19.6 mmol) was added. The resulting mixture was allowed to warm up toroom temperature and stirred for 1.5 hr. The mixture was acidified with2M hydrochloric acid and extracted with diethyl ether (300 ml). Theseparated organic layer was washed with water (100 ml×3) and dried overmagnesium sulfate. The solution was evaporated to give 5.2 g of1-(4-bromophenyl)-2,4,4,4-tetrafluoro-1,3-butanedione as a brown oil.This residue was heated with 5-hydrazino-2-pyrisinesulfonamidehydrochloride (1.10 g, 4.89 mmol) at refluxing temperature for 18 hr.After evaporation, the obtained residue was chromatographed on a columnof silica gel (500 g) eluting with ethyl acetate/hexane (1:3 to 1:1) toafford 930 mg (12%) of the title compound as a yellow solid.

¹H-NMR (DMSO-d6) δ: 8.70 (1H, dd, J=0.8 and 2.3 Hz), 8.08 (1H, dd, J=2.3and 8.4 Hz), 8.03 (1H, d, J=8.6 Hz), 7.76-7.70 (2H, m), 7.64 (2H, br s),7.42-7.36 (2H, m). MS (EI): 464 and 466 (M⁺).

5-{4-Fluoro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide(Step 3)

The title compound was prepared according to the procedure of step 3 inthe Example 4 using5-[4-fluoro-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide,instead of5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.

¹H-NMR (CDCl₃) δ: 8.90 (1H, d, J=2.0 Hz), 8.67 (1H, d, J=2.5 Hz),8.06-7.98 (3H, m), 7.86 (1H, dd, J=2.5 and 8.6 Hz), 7.65 (1H, d, J=2.0Hz), 7.37-7.31 (2H, m), 5.41 (2H, br s).

5-{4-Fluoro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamideHydrochloride (Step 4)

The title compound was prepared according to the procedure of step 2 inthe Example 6 using5-{4-fluoro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide,instead of5-{5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide.

m.p.: 145° C. (recrystallized from methanol/dichloromethane); ¹H-NMR(DMSO-d6) δ: 9.24 (1H, d, J=1.8 Hz), 8.73 (1H, d, J=2.3 Hz), 8.33 (1H,d, J=1.8 Hz), 8.15-8.08 (3H, m), 8.04 (1H, d, J=8.4 Hz), 7.63 (2H, brs), 7.47 (2H, m). MS (EI): 469 (M⁺).

Example 105-[5-[4-(1,3-Thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamideHydrochloride

5-[5-[4-(1,3-Thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 1).

The mixture of5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(400 mg, 0.8944 mmol) in 1,4-dioxane (10 mL) were added5-tributhylstannylthiazole (401 mg, 1.073 mmol), LiCl (94.8 mg, 2.236mmol) and tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.0894 mmol)at room temperature under nitrogen. The mixture was heated at refluxtemperature for 16 hours, and cooled down to room temperature, thesolvent was removed under reduced pressure and the residue was dissolvedin ethyl acetate (100 mL), washed with water (30 mL), dried over MgSO4and concentrated in vacuo. The residue was purified by flashchromatography eluting with ethyl acetate/hexane (1/1) to give titlecompound (281.3 mg, 70% yield).

¹H-NMR (CDCl₃) δ: 8.83 (s, 1H), 8.69 (d, J=1.6 Hz, 1H), 8.15 (s, 1H),8.06 (d, J=8.4 Hz, 1H), 7.93 (dd, J=2.5, 8.4 Hz, 1H), 7.65 (d, J=8.6 Hz,2H), 7.31 (d, J=8.6 Hz, 2H), 6.87 (s, 1H), 5.04 (br s, 1H).

5-[5-[4-(1,3-Thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamideHydrochloride (Step 2).

The title compound was prepared according to the procedure of Example 4using5-[5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide,instead of5-{4-chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide.

mp: 138° C. ¹H-NMR (DMSO-d6) δ: 9.14 (s, 1H), 8.75 (d, J=2.0 Hz, 1H),8.43 (s, 1H), 8.12 (dd, J=2.5, 8.4 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.79(d,J=8.6 Hz, 2H), 7.64 (br s, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.39 (s, 1H).Anal. Calcd. for C₁₈H₁₂F₃N₅O₂S₂.1HCl.0.5H₂O.0.3EtOH: C, 43.74; H, 3.12;N, 13.71. Found: C, 43.72; H, 3.10; N, 13.36.

Example 115-{4-Fluoro-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamideHydrochloride

5-{4-Fluoro-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide(Step 1)

The title compound was prepared according to the procedure of step 1 inthe Example 10 using5-[4-fluoro-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Example 8, step 1), instead of5-[5-(4-bromophenyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.

¹H-NMR (CDCl₃) δ: 8.84 (1H, s), 8.68 (1H, d, J=2.3 Hz), 8.17 (1H, s),8.07 (1H, d, J=8.4 Hz), 7.92 (1H, dd, J=2.3 and 8.6 Hz), 7.73-7.67 (2H,m), 7.36-7.30 (2H, m), 5.08 (2H, br s).

5-{4-Fluoro-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamideHydrochloride (Step 2)

The title compound was prepared according to the procedure of step 2 inthe Example 6 using5-{4-fluoro-5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide,instead of5-{5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide.

m.p.: 134° C. (recrystallized from methanol/acetone); ¹H-NMR (DMSO-d6)δ: 9.15 (1H, s), 8.75 (1H, d, J=2.3 Hz), 8.44 (1H, s), 8.12 (1H, dd,J=2.5 and 8.4 Hz), 7.85 (1H, d, J=8.4 Hz), 7.87-7.81 (2H, m), 7.65 (2H,br s), 7.52-7.45 (2H, m). MS (EI): 469 (M⁺).

Example 125-[5-Chloro-4-(1,3-thiazole-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamideHydrochloride

[(4-tert-Butyldimethylsilyloxy)-3-chloro]phenyl-1-ethanone (Step 1)

To a solution of 1-(3-chloro-4-hydroxy)phenyl-1-ethanone (18.5 g, 0.11mol, G. Leclerc et al., J. Med. Chem. 23, 738 (1980)) in DMF (300 mL),tert-butyldimethylsilylchloride (18 g, 0.12 mol) and imidazole (8.8 g,0.13 mol) was added at room temperature and the mixture was stirred for3 hours. The mixture was poured into water (300 mL) and extracted withdiethyl ether (150 mL×2), washed with water (80 mL), dried over MgSO₄and concentrated in vacuo gave clear brown oil. (33 g, quant.)

¹H-NMR (CDCl₃) δ: 7.98 (d, J=2.3 Hz, 1H), 7.75 (dd, J=2.3, 8.6 Hz, 1H),6.91 (d, J=8.6 Hz, 1H), 2.54 (s, 3H), 2.04 (s, 9H), 0.26 (s, 6H).

1-(4-tert-Butyldimethylsilyloxy)-3-chlorophenyl-4,4,4-trifluoro-1,3-butanedione(Step 2)

To a solution of hexamethyldisilazane (1.8 mL, 8.4 mmol) in THF (20 mL),n-BuLi (1.53 M in n-hexane, 5.5 mL, 8.4 mmol) was added at 0° C. andstirred for 30 min at 0° C. The mixture was cooled to −70° C. and[(4-tert-butyldimethylsilyloxy)-3-chloro]phenyl-1-ethanone (from step 1,2.0 g, 7.0 mmol) in THF (10 mL) was added dropwise and the mixture wasstirred for 1 h at −70° C. Then trifluoroacetylimidazole (0.96 mL, 8.4mmol) was added at −70° C. and the mixture was stirred for further 2hours and water (30 mL) was added. 2N aqueous HCl was added to adjust pHto 4 and extracted with ethyl acetate (100 mL×2), dried over MgSO₄, andconcentrated in vacuo gave pale red brown oil. (2.5 g, 93%).

¹H-NMR (CDCl₃) δ: 7.99 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 6.48 (d, J=8.0Hz, 1H), 6.48 (s, 1H), 1.04 (s, 9H), 0.28 (s, 6H).

5-[5-(3-Chloro-4-hydroxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 3)

To a solution of1-(4-tert-butyldimethylsilyloxy)-3-chlorophenyl-4,4,4-trifluoro-1,3-butanedione(from step 2, 423 mg, 1.1 mmol) in EtOH (8 mL),5-hydrazino-2-pyridinesulfonamide hydrochloride (300 mg, 1.3 mmol) wasadded and the mixture was refluxed for 12 hours. The mixture was cooledto room temperature and concentrated in vacuo and water (10 mL) wasadded and extracted with ethyl acetate (30 mL×2), dried over MgSO₄, andconcentrated in vacuo gave oil (452 mg). The oil was dissolved in THF (8mL) and TBAF (1.0 M in THF, 1.3 mL, 1.3 mmol) was added at 0° C. and themixture was stirred for 30 min at room temperature. The mixture waspoured into water (20 mL) and extracted with ethyl acetate (10 mL×3),dried over MgSO₄, and concentrated in vacuo. The residue was purified byflash chromatography eluting with ethyl acetate-hexane (1:2 to 1:1) togive title compound as a pale yellow powder(243 m g, 52%).

¹H-NMR (DMSO-d₆) δ: 8.71 (d, J=1.8 Hz, 1H), 8.07 (dd, J=2.5, 8.4 Hz,1H), 8.02 (d, J=8.1 Hz, 1H), 7.63 (br s, 2H), 7.47 (d, J=2.0 Hz, 1H),7.25 (s, 1H), 7.06 (d, J=2.1, 8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 7.61(dd, J=7, 1 Hz, 1H), 7.47-7.46 (m, 2H), 2.64 (s, 3H).

[4-[1-[6-(Aminosulfonyl)-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-chlorophenyl]trifluoromethanesulfonate(Step 4)

To a solution of5-[5-(3-chloro-4-hydroxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamide(from step 3, 2.4 g, 5.8 mmol) in CH₂Cl₂ (60 mL),4-dimethylaminopyridine (1.0 g, 8.4 mmol) and trifluoromethanesulfonicanhydride (1.2 mL, 7.0 mmol) was added at 0° C. and the mixture wasstirred for 30 min at room temperature. The mixture was concentrated invacuo and water (20 mL) was added and extracted with ethyl acetate (80mL), dried over MgSO₄, and concentrated in vacuo gave title compound asa brown amorphous solid (3.48 g, 100%).

¹H-NMR (CDCl₃) δ: 8.68 (d, J=2.5 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.88(dd, J=2.3, 8.4 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H),7.17 (dd, J=1.8, 8.6 Hz, 1H), 6.89 (s, 1H).

5-[5-Chloro-4-(1,3-thiazole-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamideHydrochloride (Step 5)

The title compound was prepared according to the procedure of Example 4step 3,4 using[4-[1-[6-(aminosulfonyl)-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-chlorophenyl]trifluoromethanesulfonateinstead of5-{4-chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide.

mp: 118-120° C. ¹H-NMR (DMSO-d₆) δ: 8.97 (s, 1H), 8.71 (s, 1H),8.10-8.02 (m, 3H), 7.92 (d, J=8.6 Hz, 1H), 7.51 (s, 1H), 7.18 (d, J=7.6Hz, 1H), 6.91 (s, 1H). Anal. Calcd. for C₁₈H₁₁N₅O₂F₃Cl₂S₂: C, 41.39; H,2.32; N, 13.41. Found: C, 42.80; H, 2.80; N, 12.68.

Example 135-[5-[3,5-Dichloro-4-(1,3-thiazol-5-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfoneamideHydrochloride

(4-Bromo-2,6-dichlorophenoxy)(tert-butyl)dimethylsilane (Step 1)

To a solution of 4-bromo-2,6-dichlorophenol (11.9 g, 49.2 mmol, H. Joyceet al., J. Amer. Chem. Soc., 39, 2644 (1917)) in DMF (100 mL) imidazole(5.0 g, 74 mmol) and tert-butyldimethylsilylchloride (8.9 g, 59 mmol)was added at room temperature and the mixture was stirred for 1 h. Themixture was poured into water (300 mL) and extracted with diethyl ether(100 mL×2) and washed with water (50 mL×2), dried over MgSO₄ andconcentrated in vacuo gave pale yellow oil. (15.3 g, 87%)

¹H-NMR (CDCl₃) δ: 7.40 (s, 2H), 1.04 (s, 9H), 0.28 (s, 6H).

1-[4-(tert-Butyldimethylsilyloxy)-3,5-dichlorophenyl]-1-ethanone (Step2)

To a solution of (4-bromo-2,6-dichlorophenoxy)(tert-butyl)dimethylsilane(from step 1, 15.2 g, 42.7 mmol) in diethyl ether (100 mL), n-BuLi (1.57M in n-hexane, 27.2 mL, 42.7 mmol) was added at −78° C. and the mixturewas stirred for 1 h. N,N′-dimethylacetamide (4.2 mL, 44 mmol) in THF (20mL) was added at −78° C. and the mixture was stirred for 2 hours. Themixture was added water (100 mL) and extracted with diethyl ether (50mL×3), dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash chromatography eluting with ethyl acetate-hexane(1:10) to give title compound as a pale yellow oil (4.7 g, 34%).

¹H-NMR (CDCl₃) δ: 7.87 (s, 2H), 2.55 (s, 3H), 1.06 (s, 9H), 0.32 (s,6H).

(4-Acetyl-2,6-dichlorophenyl)trifluoromathanesulfonate (Step 3)

To a solution of1-[4-(tert-butyldimethylsilyloxy)-3,5-dichlorophenyl]-1-ethanone (fromstep 2, 4.6 g, 14.5 mmol) in THF (50 mL) was added TBAF (1.0 M in THF,17.4 mL) at 0° C. and the mixture was stirred for 1 h at roomtemperature. The mixture was poured into water (50 mL) and extractedwith ethyl acetate (30 mL×2), dried over MgSO₄ and concentrated in vacuogave title compound as a yellow brown oil. The oil was dissolved inCH₂Cl₂ (100 mL) and 4-dimethylaminopyridine (2.6 g, 21 mmol) andtrifluoromethanesulfonic anhydride (2.9 mL, 17 mmol) was added at roomtemperature and the mixture was stirred for 0.5 h. The mixture wasconcentrated in vacuo and water (30 mL was added and extracted withethyl acetate (50 mL×2), dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:10) to give title compound as a white powder(2.1 g,43%).

¹H-NMR (CDCl₃) δ: 8.00 (s, 2H), 2.62 (s, 3H).

2,6-Dichloro-4-(-4,4,4-trifluoro-1,3-oxobutanoyl)phenylTrifluoromethanesulfonate (Step 4)

The title compound was prepared according to the procedure of step 2 ofExample 12 using (4-acetyl-2,6-dichlorophenyl)trifluoromathanesulfonateinstead of 1-[3-chloro-4-[(trimethylsilyl)oxy]phenyl]-1-ethanone.

¹H-NMR (CDCl₃) δ: 7.84 (s, 2H), 7.08 (br s, 1H), 6.20 (br s, 1H).

[4-[1-[6-(Aminosulfonyl)-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2,6-dichlorophenyl]trifluoromethanesulfonate(Step 5)

The title compound was prepared according to the procedure of Example 4using 2,6-Dichloro-4-(-4,4,4-trifluoro-1,3-oxobutanoyl)phenyltrifluoromethanesulfonate instead of1-(4-bromophenyl)-4,4,4-trifluoro-1,3-butanedione.

¹H-NMR (CDCl₃) δ: 8.71 (d, J=2.3 Hz, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.91(dd, J=2.5, 8.4 Hz, 1H), 7.36 (s, 2H), 6.91 (s, 1H), 5.22 (br s, 2H).

5-[5-[3,5-Dichloro-4-(1,3-thiazol-5-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfoneamideHydrochloride (Step 6)

The title compound was prepared according to the procedure of Example 6using[4-[1-[6-(aminosulfonyl)-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2,6-dichlorophenyl]trifluoromethanesulfonateinstead of5-{5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide.

mp: 123-125° C. ¹H-NMR (DMSO-d₆) δ: 9.36 (s, 1H), 8.85 (d, J=2.3 Hz,1H), 8.18 (dd, J=2.5, 8.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (s, 1H),7.72 (s, 2H), 7.53 (s, 1H). Anal. Calcd. for C₁₈H₁₁N₅O₂F₃Cl₃S₂: C,38.83; H, 1.99; N, 12.58. Found: C, 38.80; H, 2.49; N, 11.36.

Example 145-[5-Chloro-4-(1,3-thiazole-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamideHydrochloride

The title compound was prepared according to the procedure of Example 10using[4-[1-[6-(aminosulfonyl)-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-chlorophenyl]trifluoromethanesulfonatefrom step 4 of example 12 instead of5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.

mp: 167-168° C. 1H-NMR (DMSO-d₆) δ: 9.28 (s, 1H), 8.81 (d, J=2.0 Hz,1H), 8.31 (s, 1H), 8.15 (dd, J=2.5, 8.4 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H),7.79 (d, J=8.1 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.68 (br s, 1H), 7.48(s, 1H), 7.36 (dd, J=1.8, 8.1 Hz, 1H), 5.76 (s, 2H), Anal. Calcd. forC18H11N5O2F3Cl2S2: C, 41.39; H, 2.32; N, 13.41. Found: C, 40.88; H,2.35; N, 13.02.

Example 155-(5-(3-Fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamideHydrochloride

1-(3-Fluoro-4-hydroxyphenyl)-1-ethanone (Step 1)

1-(3-Fluoro-4-hydroxyphenyl)-1-ethanone was prepared according to theprocedure described in J.Med.Chem., 23, 738-744 (1980).

4-Acetyl-2-fluorophenyl Trifluoromethanesulfonate (Step 2)

To a stirred solution of 1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (3.9 g,25.30 mmol) in pyridine (86 ml) was added trifluoromethanesulfonicanhydride (5.5 ml, 32.89 mmol) dropwise at 0° C. under nitrogen. Thereaction mixture was stirred at room temperature for 17 h. This waspoured onto water and extracted with ethyl acetate. The extracts waswashed with 2N HCl, brine, dried (MgSO₄), and concentrated to afford7.38 g as a brown oil. The crude material was used for next stepdirectly.

¹H-NMR (CDCl₃) δ: 7.88-7.80 (2H, m), 7.49-7.43 (1H, m), 2.63 (3H, s).

4-(1-(6-Aminosulfonyl-3-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl)-2-fluorophenylTrifluoromethanesulfonate (Step 3)

To a stirred solution of hexamethyldisilazane (6.4 ml, 30.36 mmol) intetrahydrofuran (65 ml) was added n-butyllithium (19.3 ml, 30.36 mmol)dropwise at 0° C. under nitrogen. The reaction mixture was stirred at 0°C. for 30 min. Then cooled to −78° C., to the mixture was added asolution of 4-acetyl-2-fluorophenyltrifluoromethanesulfonate (7.24 g,25.30 mmol) in tetrahydrofuran (30 ml) dropwise and stirred at −78° C.for 1 h. Then 1-trifluoroacetylimidazole (3.5 ml, 30.36 mmol) was addedto the mixture at same temperature and the mixture was stirred at −78°C. for 3 h. This was quenched by water and the pH was adjusted to pH4-5, extracted with ethyl acetate. The extracts was dried (MgSO₄) andconcentrated. This was purified on silica gel eluting with ethylacetate/hexane (1:10/1:8/1:4) to afford2-fluoro-4-(4,4,4-trifluoro-3-oxobutanoyl)phenyltrifluoromethanesulfonate(3.0 g) as a red oil. A mixture of2-Fluoro-4-(4,4,4-trifluoro-3-oxobutanoyl)phenyltrifluoromethanesulfonate(1.0 g, 2.62 mmol) and 5-hydrazino-2-pyridinesulfonamide hydrochloride(823 mg, 3.66 mmol) in ethanol (35 ml) was stirred at reflux for 15 h.After cooling, the solvent was removed and the residue was diluted withethyl acetate, washed with water. The extracts was dried (MgSO₄) andconcentrated. This was purified on silica gel eluting with ethylacetate/hexane (1:10/1:8/1:6/1:3) to afford 886 mg_(63.3%) of the titledcompound as a white amorphous.

¹H-NMR (CDCl₃) δ: 8.66 (1H, d, J=2.5 Hz), 8.08 (1H, d, J=8.4 Hz), 7.88(1H, dd, J=8.4, 2.5 Hz), 7.46-7.40 (1H, m), 7.31-7.25 (1H, m), 7.13-7.10(1H, m), 6.90 (1H, s), 6.28 (2H, br.s).

5-(5-(3-Fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide(Step 4)

A mixture of4-(1-(6-aminosulfonyl-3-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl)-2-fluorophenyltrifluoromethanesulfonate(440 mg, 0.823 mmol), 5-tributylstannyl-1,3-thiazol (370 mg, 0.988mmol), tetrakis(triphenylphosphine)palladium (95 mg, 0.082 mmol),lithium chloride (87 mg, 2.058 mmol) in 1,4-dioxane (10 ml) was stirredat reflux for 16 h. After cooling, the mixture was diluted with ethylacetate, washed with water. The organic layer was dried (MgSO₄) andconcentrated. This was purified on silica gel eluting with ethylacetate/hexane (1:3/1:2) to afford 236 mg (61.1%) of the titled compoundas a white solid.

¹H-NMR (CDCl₃) δ: 8.91 (1H, s), 8.69-8.68 (1H, m), 8.32 (1H, s), 8.07(1H, dd, J=8.4, 0.7 Hz), 7.93 (1H, dd, J=8.6, 2.5 Hz), 7.67 (1H, t,J=7.7 Hz), 7.18 (1H, dd, J=10.9, 1.6 Hz), 7.06 (1H, dd, J=8.1, 1.8 Hz),6.89 (1H, s), 6.08 (2H, s).

5-(5-(3-Fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamideHydrochloride (Step 5)

5-(5-(3-Fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide(236 mg, 0.50 mmol) was dissolved with HCl—MeOH and the solvent wasremoved. The residue was washed with ethyl acetate to afford 233 mg(92.1%) of the titled compound as a slight yellow solid.

¹H-NMR (DMSO) δ: 9.26 (1H, s), 8.79 (1H, d, J=1.8 Hz), 8.48 (1H, s),8.13 (1H, dd, J=8.6, 2.5 Hz), 8.04 (1H, d, J=8.4 Hz), 7.95 (1H, t, J=8.1Hz), 7.66 (2H, br.s), 7.57-7.52 (1H, m), 7.46 (1H, s), 7.27 (1H, dd,J=8.1, 1.8 Hz); IR (KBr) ν: 1736, 1474, 1394, 1342, 1242, 1177, 1144,974 cm⁻¹; mp: 173-176° C.

Example 165-[4-Chloro-5-[3-chloro-4-(1,3-thiazol-5-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamide

1-[4-(tert-Butyldimethylsilyloxy)-3-chlorophenyl]-2-chloro-4,4,4-trifluoro-1,3-butanedione(Step 1)

To a solution of1-(4-tert-Butyldimethylsilyloxy)-3-chlorophenyl-4,4,4-trifluoro-1,3-butanedione(from step 2 of Example 12, 1.9 g, 5 mmol) in CH₂Cl₂ (15 mL) was addedSO₂Cl₂ (680 mg, 5 mmol) in CH₂Cl₂ (5 mL) at 0° C. and the mixture wasstirred for 30 min at room temperature. The mixture was added 10%aqueous K₂CO₃ (25 mL) and stirred 5 min. The mixture was acidified bythe addition of 2N aqueous HCl and extracted with CH₂Cl₂ (30 mL×3),dried over MgSO₄, and concentrated in vacuo gave orange color oil. (1.3g) This was used next step without further purification.

5-[4-Chloro-5-(3-chloro-4-hydroxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 2)

The title compound was prepared according to the procedure of Example 12step 3 using1-[4-(tert-butyldimethylsilyloxy)-3-chlorophenyl]-2-chloro-4,4,4-trifluoro-1,3-butanedioneinstead of1-(4-tert-butyldimethylsilyloxy)-3-chlorophenyl-4,4,4-trifluoro-1,3-butanedione.This was used next step without further purification.

MS (EI): m/z 452 (M⁺).

[4-[1-[6-(Aminosulfonyl)-3-pyridinyl]-4-chloro-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-chlorophenyl]trifluoromethanesulfonate(Step 3)

The title compound was prepared according to the procedure of step 4 ofExample 12 step 4 using5-[4-chloro-5-(3-chloro-4-hydroxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamideinstead of5-[5-(3-chloro-4-hydroxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamide.

¹H-NMR (CDCl₃) δ: 8.62 (m, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.83 (m, 1H),7.59 (d,J=1.8 Hz, 1H), 7.49 (d,J=8.4 Hz, 1H), 7.57-7.40 (m, 1H), 5.10(s, 2H).

5-[4-Chloro-5-[3-chloro-4-(1,3-thiazol-5-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamide(Step 4)

The title compound was prepared according to the procedure of Example 15step 4 using[4-[1-[6-(aminosulfonyl)-3-pyridinyl]-4-chloro-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-chlorophenyl]trifluoromethanesulfonateinstead of4-(1-(6-aminosulfonyl-3-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl)-2-fluorophenyltrifluoromethanesulfonate.

mp: 191-193° C. ¹H-NMR (CDCl₃) δ: 8.94 (s, 1H), 8.65 (d, J=2.5 Hz, 1H),8.21 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.92 (dd, J=2.5, 8.4 Hz, 1H), 7.64(d, J=7.9 Hz, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.18 (dd, J=1.6, 8.0 Hz, 1H),5.13 (s, 214). Anal. Calcd. for C₁₈H₁₀N₅O₂F₃Cl₂S₂: C, 41.55; H, 1.94; N,13.46. Found: C, 41.62; H, 2.15; N, 12.58.

Example 176-[5-[3-Methyl-4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-pyridinesulfonamideHydrochloride

2-Bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone (Step 1)

To a stirred solution of 4′-hydroxy-2′-methylacetophenone (4.5 g, 30.0mmol) in dioxane (7 ml) was added a solution of bromine (4.87 g, 30.5mmol) in dioxane (28 ml) dropwise at room temperature. After addition,the mixture was stirred at room temperature for 30 minutes. The volatilewas evaporated in vacuo, and the residue was used for next reactionwithout further purification. (5.57 g, 81% yield).

¹H-NMR (CDCl₃) δ: 7.71 (d, J=9 Hz, 1H), 6.76-6.71 (m, 2H), 5.71 (s, 1H),4.40 (s, 2H), 2.55 (s, 3H).

3-Methyl-4-(1,3-thiazol-4-yl)phenol (Step 2)

To a stirred solution of phosphorus pentasulfide (6.0 g, 13.5 mmol) indioxane (60 ml) was added formamide (7.2 g, 160 mmol), and the mixturewas heated at reflux temperature for 2 hours. The reaction mixture wascooled down to room temperature, and the solution was decanted away fromsolids. To a stirred solution of2-bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone from step 1 (2.4 g, 10.5mmol) in dioxane (20 ml) was added the thioformamide solution, and themixture was heated at reflux temperature for 6 hours. The reactionmixture was cooled down to room temperature, and made basic by additionof 0.5M NaOH aqueous solution. The whole was extracted with ethylacetate. The organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with ethyl acetate-hexane (1:4) to give title compound (1.54 g,77% yield).

¹H-NMR (DMSO-d₆) δ: 9.46 (s, 1H), 9.10 (d, J=2 Hz, 1H), 7.59 (d, J=2 Hz,1H), 7.39 (d, J=8 Hz, 1H), 6.67-6.61 (m, 2H), 2.30 (s, 3H).

3-Methyl-4-(1,3-thiazol-4-yl)phenyl Trifluoromethanesulfonate (Step 3)

To a stirred solution of 3-methyl-4-(1,3-thiazol-4-yl)phenol from step 2(1.54 g, 8.05 mmol) in CH₂Cl₂ (48 ml) was added 2,6-lutidine (1.04 g,9.66 mmol), 4-dimethylaminopyridine (0.20 g, 1.61 mmol),trifluoromethanesulfonic anhydride (2.73 g, 9.66 mmol) at −30° C. undernitrogen, and the mixture was stirred for 1 hour, and then allowed towarm up to room temperature for 2 hours. The reaction mixture wasdiluted with water and the whole was extracted with CH₂Cl₂. The organiclayer was washed with brine, dried over MgSO₄, and concentrated invacuo, and the residue was used for next reaction without furtherpurification. (2.60 g, 99% yield).

Mass (m/e) 323 (M⁺).

1-[3-Methyl-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 4)

To a stirred solution of 3-methyl-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate from step 3 (2.60 g, 8.05 mmol) in dioxane (75ml) was added tributyl(1-ethoxyvinyl)tin (3.5 g, 9.66 mmol),tetrakis(triphenylphosphine) palladium (930 mg, 0.805 mmol), lithiumchloride (850 mg, 20.0 mmol), and the mixture was heated at refluxtemperature for 8 hours. The reaction mixture was cooled down to roomtemperature, and diluted with ethyl acetate. The whole was washed withsaturated potassium fluoride aqueous solution, and the precipitate wasremoved by filteration through celite. The resulting solution wasextracted with ethyl acetate. The organic layer was concentrated invacuo. To the residue was added THF (50 ml), 2N HCl aqueous solution (50ml), and the mixture was heated at reflux temperature for 8 hours. Thereaction mixture was cooled down to room temperature, made neutral byaddition of NaHCO₃, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:5) to give title compound (714 mg, 41% yield).

¹H-NMR (CDCl₃) δ: 8.92 (d, J=2 Hz, 1H), 7.89-7.84 (m, 2H), 7.74 (d, J=8Hz, 1H), 7.44 (d, J=2 Hz, 1H), 2.64 (s, 3H), 2.53 (s, 3H).

4,4,4-Trifluoro-1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 5)

To a stirred solution of ethyl trifluoroacetate (500 mg, 3.52 mmol) intert-butyl methyl ether (4 ml) was added sodium methoxide (28 wt.%solution in methanol; 0.9 ml, 4.0 mmol) over 2 min. A solution of1-[3-methyl-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone from step 4 (714 mg,3.33 mmol) in t-butylmethylether (6 ml) was added dropwise over 5minutes, and the mixture was stirred for 20 hours. 2N HCl (10 ml) wasadded, and the whole was extracted with ethyl acetate. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo, andthe residue was used for next reaction without further purification.(1.05 g, 99% yield).

¹H-NMR (CDCl₃) δ: 8.93 (d, J=2 Hz, 1H), 7.88-7.78 (m, 3H), 7.49 (d, J=2Hz, 1H), 6.61 (s, 1H), 2.56 (s, 3H).

5-[3-Methyl-4-(4-thiazolyl)phenyl]-1-[2-(5-sulfamoyl)pyridyl]-3-trifluoromethyl-1H-pyrazole(Step 6)

The title compound was prepared according to the procedure of Example 1,step 2 using4,4,4-trifluoro-1-[3-methyl-4-(4-thiazolyl)phenyl]butane-1,3-dioneinstead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione.

mp: 142.0-143.0° C. ¹H-NMR (CDCl₃) δ: 8.91 (d, J=2 Hz, 1H), 8.80 (d, J=2Hz, 1H), 8.30 (dd, J=3, 9 Hz, 1H), 7.87 (d, J=9 Hz, 1H), 7.59 (d, J=8Hz, 1H), 7.41 (d, J=2 Hz, 1H), 7.29-7.26 (m, 1H), 7.09 (d, J=8 Hz, 1H),6.80 (s, 1H), 5.26 (brs, 2H), 2.45 (s, 3H).Anal.Calcd.for.C₁₉H₁₄F₃N₅O₂S₂: C, 49.03; H, 3.03; N, 15.05. Found: C,48.95; H, 3.36; N, 14.68. MS (EI): m/z 465 (M⁺).

5-[3-Methyl-4-(4-thiazolyl)phenyl]-1-[2-(5-sulfamoyl)pyridyl]-3-trifluoromethyl-1H-pyrazoleHydrochloride. (Step 7)

5-[3-Methyl-4-(4-thiazolyl)phenyl]-1-[2-(5-sulfamoyl)pyridyl]-3-trifluoromethyl-1H-pyrazole(0.1g, 0.21 mmol) was dissolved in 10% methanolic HCl (2 mL), and volatileswere removed by evaporation. The residue was recrystallized frommethanol/dichloromethane to give the title compound (0.09 g, 85.7%yield).

mp: 138.0-140.0° C. ¹H-NMR (DMSO-d₆) δ: 9.22 (d, J=2 Hz, 1H), 8.73 (d,J=2 Hz, 1H), 8.45 (dd, J=2, 9 Hz, 1H), 8.02 (d, J=9 Hz, 1H), 7.94 (d,J=2 Hz, 1H), 7.76 (brs, 2H), 7.62 (d, J=8 Hz, 1H), 7.41 (brs, 1H), 7.33(s, 1H), 7.13 (d, J=8 Hz, 1H), 2.42 (s, 3H).Anal.Calcd.for.C₁₉H₁₄F₃N₅O₂S₂,HCl,0.7H₂O: C, 44.35; H, 3.21; N, 13.61.Found: C, 44.02; H, 3.26; N, 13.37. MS (EI): m/z 465 (M⁺).

Example 185-[5-[3-Methyl-4-(1,3-thiazol-4-yl)phenyl]-3-trifluoromethyl-1H-pyrazol-1-yl]-2-pyridinesulfonamideHydrochloride

The title compound was prepared according to the procedure of Example 17using 5-hydrazino-2-pyridinesulfonamide hydrochloride (Example 6)instead of 2-hydrazino-5-pyridinesulfonamide dihydrochloride.

mp: amorphous ¹H-NMR (DMSO-d₆) δ: 9.21 (d, J=2.0 Hz, 1H), 8.73 (d, J=2.5Hz, 1H), 8.12 (dd, J=2.5, 8.4 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.95 (d,J=1.8 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.62 (br s, 2H), 7.43 (s, 1H),7.34 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 2.48 (s, 3H). Anal. Calcd. forC₁₉H₁₅N₅O₂F₃ClS₂: C, 45.47; H, 3.01; N, 13.95. Found: C, 45.83; H, 3.52;N, 13.19.

Example 195-(4-Ethyl-5-(3-fluoro-4-(1,3-thiazol-4-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide

4-Bromo-3-fluorobenzoic acid (Step 1)

A mixture of 4-bromo-3-fluorotoluene (15.0 g, 79.35 mmol) and sodiumhydroxide (3.3 g, 82.53 mmol) in pyridine (80 ml) and water (160 ml) wasstirred at reflux. Potassium permanganese (52.7 g, 333.28 mmol) wasadded to the mixture over 30 min. The resulting suspension was heated atreflux for 3 h. The mixture was filtered through celite. The celite waswashed with hot water, followed by ethyl acetate. The cooled aqueouslayer was acidified to pH 1 with conc.HCl and extracted with ethylacetate. The extracts was dried (MgSO₄) and concentrated to afford 15.0g (86.3%) of the titled compound as a white crystal. The compound wasused for the next reaction directly.

¹H-NMR (CDCl₃) δ: 7.81-7.71 (2H, m), 7.65-7.60 (1H, m).

4-Bromo-3-fluoro-N-methoxy-N-methylbenzamide (Step 2)

To a stirred solution of 4-bromo-3-fluorobenzoic acid (5.0 g, 22.83mmol) in dichloromethane (100 ml) was added WSC (8.8 g, 45.66 mmol),N,O-dimethylhydroxylamine hydrochloride (4.5 g, 45.66 mmol) and stirredat room temperature for 5 h. The solvent was removed and the residue wasdiluted with ethyl acetate. The organic layer was washed with water,dried (MgSO₄), and concentrated to afford 5.47 g of the titled compoundas a yellow oil. The compound was used for the next reaction directly.

¹H-NMR (CDCl₃) δ: 7.63-7.58 (1H, m), 7.53-7.49 (1H, m), 7.43-7.39 (1H,m), 3.55 (3H, s), 3.37 (3H, s).

1-(4-Bromo-3-fluorophenyl)-1-butanone (Step 3)

To a stirred solution of 4-Bromo-3-fluoro-N-methoxy-N-methylbenzamide(3.0 g, 12.19 mmol) in tetrahydrofuran (35 ml) was added 2Mn-propylmagnesium bromide (12.2 ml, 24.38 mmol) dropwise under nitrogenat 0° C. The reaction mixture was stirred at room temperature for 2 h.This was quenched by sat. ammonium chloride and stirred at rt for 30min. The organic layer was separated and the aqueous layer was extractedwith ethyl acetate. The extracts was dried (MgSO₄) and concentrated.This was purified on silica gel eluting with ethyl acetate/hexane (1:10)to afford 2.44 g (81.7%) of the titled compound as a slight yellow oil.

¹H-NMR (CDCl₃) δ: 7.71-7.59 (3H, m), 2.90 (2H, t, J=7.4 Hz), 1.77 (2H,m), 1.00 (3H, t, J=7.4 Hz).

5-(5-(4-Bromo-3-fluorophenyl)-4-ethyl-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide(Step 4)

To a stirred solution of hexamethyldisilazane (2.5 ml, 11.75 mmol) intetrahydrofuran (25 ml) was added n-butyllithium (7.5 ml, 11.75 mmol)dropwise at 0° C. under nitrogen. The reaction mixture was stirred atroom temperature for 30 min. Then cooled to −78° C., to the mixture wasadded a solution of 1-(4-bromo-3-fluorophenyl)-1-butanone (2.4 g, 9.79mmol) in tetrahydrofuran (12 ml) dropwise and stirred at rt for 1 h.Then 1-trifluoroacetylimidazole (1.3 ml, 11.75 mmol) was added to themixture at same temperature, the mixture was stirred at rt for 5 h. Thiswas quenched by water and the pH was adjusted to pH 4-5, extracted withethyl acetate. The extracts was dried (MgSO₄) and concentrated. This waspurified on silica gel eluting with ethyl acetate/hexane (1:20/1:15) toafford 2.7 g (80.9%) as a yellow oil. A mixture of1-(4-bromo-3-fluorophenyl)-2-ethyl-4,4,4-trifluoro-1,3-butanedione (1.5g, 4.40 mmol) and 5-hydrazino-2-pyridinesulfonamide hydrochloride (1.28g, 5.72 mmol) in ethanol (60 ml) was stirred at reflux for 3 h. Aftercooling, the solvent was removed and the residue was diluted with ethylacetate, washed with water. The extracts was dried (MgSO₄) andconcentrated. This was purified on silica gel eluting with ethylacetate/hexane (1:10/1:5/1:4) to afford 1.64 g (75.6%) of the titledcompound as a white amorphous.

¹H-NMR (CDCl₃) δ: 8.58-8.57 (1H, m), 7.99-7.95 (1H, m), 7.79 (1H, dd,J=8.6, 2.5 Hz), 7.70-7.64 (1H, m), 7.05 (1H, dd, J=8.6, 1.8 Hz),6.91-6.88 (1H, m), 5.40 (2H, br.s), 2.56 (2H, q, J=7.6H), 1.14 (3H, t,J=7.6 Hz).

5-(4-Ethyl-5-(3-fluoro-4-(1,3-thiazol-4-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide(Step 5)

A mixture of5-(5-(4-bromo-3-fluorophenyl)-4-ethyl-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide(450 mg, 0.912 mmol), 4-tributylstannyl-1,3-thiazol (410 mg, 1.095mmol), tetrakis(triphenylphosphine)palladium (105 mg, 0.091 mmol),lithium chloride (97 mg, 2.281 mmol) in 1,4-dioxane (11 ml) was stirredat reflux for 17 h. After cooling, the mixture was diluted with ethylacetate, washed with water. The organic layer was dried (MgSO₄) andconcentrated. This was purified on silica gel eluting with ethylacetate/hexane (1:3/1:2) to afford 350 mg (77.1%) of the titled compoundas a yellow solid.

¹H-NMR (CDCl₃) δ: 8.91-8.90 (1H, m), 8.61-8.60 (1H, m), 8.39-8.33 (1H,m), 7.97-7.92 (2H, m), 7.85-7.80 (1H, m), 7.14-7.05 (2H, m), 5.28 (2H,br.s), (2H, q, J=7.6 Hz), 1.16 (3H, t, J=7.6 Hz); IR (KBr) ν: 1470,1448,1354,1292, 1178, 1157, 1128, 1076 cm⁻¹; mp: 182-185° C.

Example 205-(4-Ethyl-5-(3-fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide

5-(4-Ethyl-5-(3-fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide(Step 1)

A mixture of5-(5-(4-bromo-3-fluorophenyl)-4-ethyl-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamidefrom step 4 of Example 19 (450 mg, 0.912 mmol),5-tributylstannyl-1,3-thiazol (410 mg, 1.095 mmol),tetrakis(triphenylphosphine)palladium (105 mg, 0.091 mmol), lithiumchloride (97 mg, 2.281 mmol) in 1,4-dioxane (11 ml) was stirred atreflux for 5 h. After cooling, the mixture was diluted with ethylacetate, washed with water. The organic layer was dried (MgSO₄) andconcentrated. This was purified on silica gel eluting with ethylacetate/hexane (1:3/1:2) to afford 220 mg (48.5%) of the titled compoundas a slight yellow solid.

¹H-NMR (CDCl₃) δ: 8.92 (1H, s), 8.58 (1H, d, J=2.6 Hz), 8.33 (1H, s),8.00 (1H, d, J=8.4 Hz), 7.85 (1H, dd, J=8.4, 2.4 Hz), 7.73 (1H, t, J=7.7Hz), 7.15-7.06 m), 6.26 (2H, br.s), 2.60 (2H, q, J=7.7 Hz), 1.17 (3H, t,J=7.7 Hz). IR (KBr) ν: 1564, 1472, 1445, 1331, 1285, 1074, 835 cm⁻¹; mp:189-191° C.

Example 215-(5-(3-Fluoro-4-(1,3-thiazol-4-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamideHydrochloride

1-(2-Fluoro-4-hydroxyphenyl)-1-ethanone (Step 1)

To a stirred suspension of aluminum chloride (42 g, 312 mmol) in1,2-dichloroethane (100 ml) was added 3-fluorophenol (31 g, 276 mmol)dropwise at 0° C. After addition, acetyl chloride (24 g, 306 mmol) wasadded dropwise and then the mixture was heated at reflux temperature for16 hours. The mixture was cooled down to room temperature, and pouredinto ice. The whole was extracted with diethylether. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was recystallized with hexane to give title compound (3.57 g, 8%yield).

¹H-NMR (CDCl₃) δ: 7.88-7.82 (m, 1H), 6.74 (dd, J=9, 2 Hz, 1H), 6.64 (dd,J=13, 2 Hz, 1H), 2.62 (d, J=5 Hz, 3H).

2-Bromo-1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (Step 2)

To a stirred solution of 1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (2.56g, 16.6 mmol) in dioxane (4 ml) was added a solution of bromine (2.70 g,16.9 mmol) in dioxane (15 ml) dropwise, and the mixture was stirred atroom temperature for 3 hours. The volatile was evaporated in vacuo, andthe residue was used for next reaction without further purification.(2.4 g, 62% yield).

¹H-NMR (CDCl₃) δ: 7.95-7.89 (m, 1H), 6.73 (dd, J=9, 2 Hz, 1H), 6.63 (dd,J=13, 3 Hz, 1H), 5.96 (s, 1H), 4.48 (d, J=3 Hz, 2H).

3-Fluoro-4-(1,3-thiazol-4-yl)phenol (Step 3)

To a stirred solution of phosphorus pentasulfide (4.0 g, 9.0 mmol) indioxane (40 ml) was added formamide (4.8 g, 106 mmol), and the mixturewas heated at reflux temperature for 2 hours. The reaction mixture wascooled down to room temperature, and the solution was decanted away fromsolids. To a stirred solution of2-bromo-1-(2-fluoro-4-hydroxyphenyl)-1-ethanone (1.2 g, 5.15 mmol) indioxane (14 ml) was added the thioformamide solution, and the mixturewas heated at reflux temperature for 6 hours. The reaction mixture wascooled down to room temperature, and made basic by addition of 2N NaOHaqueous solution. The whole was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo. The residue was purified by flash chromatography eluting withethyl acetate-exane (1:4) to give title compound (864 mg, 86% yield).

¹H-NMR (DMSO-d₆) δ: 10.03 (s, 1H), 9.04 (d, J=2 Hz, 1H), 7.89-7.83 (m,1H), 7.67-7.64 (m, 1H), 6.64-6.53 (m, 2H).

3-Fluoro-4-(1,3-thiazol-4-yl)phenyl Trifluoromethanesulfonate (Step 4)

To a stirred solution of 3-fluoro-4-(1,3-thiazol-4-yl)phenol (864 mg,4.43 mmol) in CH₂Cl₂ (27 ml) was added 2,6-lutidine (570 mg, 5.32 mmol),4-dimethylaminopyridine (108 mg, 0.89 mmol), trifluoromethanesulfonicanhydride (1.5 g, 5.32 mmol) at −30° C. under nitrogen, and the mixturewas stirred for 1 hour, and then allowed to warm up to room temperaturefor 2 hours. The reaction mixture was diluted with water and the wholewas extracted with CH₂Cl₂. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo, and the residue was usedfor next reaction without further purification. (1.45 g, 99% yield).

1-[3-Fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (Step 5)

To a stirred solution of 3-fluoro-4-(1,3-thiazol-4-yl)phenyltrifluoromethanesulfonate (1.45 g, 4.43 mmol) in dioxane (42 ml) wasadded tributyl(1-ethoxyvinyl)tin (1.92 g, 5.32 mmol),tetrakis(triphenylphosphine) palladium (512 mg, 0.44 mmol), lithiumchloride (466 mg, 11.0 mmol), and the mixture was heated at refluxtemperature for 16 hours. The reaction mixture was cooled down to roomtemperature, and diluted with ethyl acetate. The whole was washed withsaturated potassium fluoride aqueous solution, and the precipitate wasremoved by filteration through celite. The resulting solution wasextracted with ethyl acetate. The organic layer was concentrated invacuo. To the residue was added THF (20 ml), 2N HCl aqueous solution (20ml), and the mixture was heated at reflux temperature for 8 hours. Thereaction mixture was cooled down to room temperature, made neutral byaddition of NaHCO₃, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:5) to give title compound (666 mg, 68% yield).

¹H-NMR (CDCl₃) δ: 8.90-8.89 (m, 1H), 8.41-8.35 (m, 1H), 7.99-7.97 (m,1H), 7.83 (dd, J=8, 2 Hz, 1H), 7.75 (dd, J=12, 2 Hz, 1H), 2.63 (s, 3H).

4,4,4-Trifluoro-1-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione(Step 6)

To a stirred solution of1-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (666 mg, 3.01 mmol),ethyl trifluoroacetate (470 mg, 3.31 mmol) in t-butylmethylether (40 ml)was added sodium methoxide (28 wt.% solution in methanol; 0.8 ml, 3.6mmol) over 5 minutes, and the mixture was stirred for 20 hours. Themixture was made neutral by addition of 2N HCl, and the whole wasextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo. The residue was used fornext reaction without further purification. (1.06 g, 99% yield).

5-(5-(3-Fluoro-4-(1,3-thiazol-4-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide(Step 7)

A suspension of4,4,4-trifluoro-1-(3-fluoro-4-(1,3-thiazol-4-yl)phenyl)-1,3-butanedione(503 mg, 1.59 mmol) and 5-hydrazino-2-pyridinesulfonamide hydrochloride(392 mg, 1.74 mmol) in ethanol (22 ml) was stirred at reflux for 28 h.After cooling, the solvent was removed and the residue was added water,extracted with ethyl acetate. The extracts was dried (MgSO₄) andconcentrated. This was purified on silica gel eluting with ethylacetate/hexane (1:4/1:3/1:2) to afford 172 mg (23.0%) of the titledcompound as a yellow solid.

¹H-NMR (CDCl₃) δ: 8.89 (1H, d, J=1.6 Hz), 8.69 (1H, d, J=1.8 Hz),8.30-8.24 (1H, m), 8.02-7.99 (1H, m), 7.91-7.86 (2H, m), 7.14-7.08 (2H,m), 6.88 (1H, s), 5.54 (2H, s).

5-(5-(3-Fluoro-4-(1,3-thiazol-4-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamideHydrochloride (Step 8)

5-(5-(3-Fluoro-4-(1,3-thiazol-4-yl)phenyl)-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide(172 mg, 0.37 mmol) was dissolved with HCl-MeOH and the solvent wasremoved. The residue was washed with ethyl acetate to afford 120 mg(64.1%) of the titled compound as a slight yellow solid.

¹H-NMR (DMSO) δ: 9.27 (1H, d, J=1.5 Hz), 8.78-8.77 (1H, m), 8.21-8.02(4H, m), 7.64 (2H, br.s), 7.49 (1H, dd, J=12.2, 1.5 Hz), 7.45 (1H, s),7.28 (1H, dd, J=8.2, 1.8 Hz). IR (KBr) ν: 1474, 1342, 1240, 1178, 1136,974 cm⁻¹; mp: amorphous

Example 225-(5-(3-Chloro-4-(2-furyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide

3-Hydrazino-2-sulfamylpyridine hydrochloride(70 mg, 0.31 mmol) and4,4,4-trifluoro-1-(3-dichloro-4-furylphenyl)-1,3-butanedione (100 mg,0.32 mmol) were dissolved in ethanol (20 mL). The reaction mixture wasrefluxed overnight. The reaction mixture was cooled to room temperature,concentrated. The crude product was dissolved in EtOAc (100 mL) andwashed with NaHCO₃ (saturated, 100 mL). The organic layer was dried(MgSO₄) and concentrated to give the crude solid. The crude product waspurified by flash chromatography eluting with ethyl acetate/hexane (1/4)to provide the desired product as a white solid (127 mg, 85.8% yield).

The chemical structures of the compounds of Formula (I) prepared in theExamples 1 to 22, are summarized in the following table. In the table,“Fu” represents furyl, “Thz” represents 1,3-thiazolyl and “Oxz”represents oxazolyl.

Following formula [AX]

[AX] is a heteoaryl moiety selected from the group consisting of

TABLE (I)

Ex. # A R¹ R² R³ R⁴ X¹ X² X³ X⁴ 1 A12 2-Fu NH₂ CF₃ H H H H H 2 A11 2-FuNH₂ CF₃ H H H H H 3 A11 2-Oxz NH₂ CF₃ H H Cl H H 4 A11 4-Thz NH₂ CF₃ ClH H H H 5 A11 4-Thz NH₂ CF₃ H H CF₃ H H 6 A11 4-Thz NH₂ CF₃ H H H H H 7A11 4-Thz NH₂ CF₃ CH₃CH₂ H H H H 8 A11 5-Thz NH₂ CF₃ CH₃CH₂ H H H H 9A11 4-Thz NH₂ CF₃ F H H H H 10 A11 5-Thz NH₂ CF₃ H H H H H 11 A11 5-ThzNH₂ CF₃ F H H H H 12 A11 4-Thz NH₂ CF₃ H H Cl H H 13 A11 5-Thz NH₂ CF₃ HCl Cl H H 14 A11 5-Thz NH₂ CF₃ H H Cl H H 15 A11 5-Thz NH₂ CF₃ H H F H H16 A11 5-Thz NH₂ CF₃ Cl H Cl H H 17 A12 4-Thz NH₂ CF₃ H H CH₃ H H 18 A114-Thz NH₂ CF₃ H H CH₃ H H 19 A11 4-Thz NH₂ CF₃ CH₃CH₂ H F H H 20 A115-Thz NH₂ CF₃ CH₃CH₂ H F H H 21 A11 4-Thz NH₂ CF₃ H H F H H 22 A11 2-FuNH₂ CF₃ H H Cl H H

What is claimed is:
 1. A compound having the formula

R¹ is furyl, thiazolyl or oxazolyl; R² is NH₂; R³ is trifluoroomethyl;R⁴ is hydrogen, fluoro or ethyl; X¹ and X² are independently hydrogen orchloro; and X³ and X⁴ are hydrogen.
 2. A compound according to claim 1selected from the group consisting of5-(5-(4-(2-furyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-(3-chloro-4-(1,3-oxazol-2-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(4-chloro-5-(4-(1,3-thiazol-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-(4-(1,3-thiazol-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulformamide;5-(5-ethyl-(4-(1,3-thiazol-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(4-ethyl-5-(4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(4-fluoro-5-(4-(1,3-thiazol-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-(4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(4-fluoro-5-(4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-chloro-(4-(1,3-thiazol-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-chloro-(4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(4-chloro-5-(3-chloro-4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-(3-methyl-4-(1,3-thiazol-4-yl)phenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(4-ethyl-5-(3-fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-(3-chloro-4-(2-furyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;and salts thereof.
 3. A compound according to claim 1 selected from thegroup consisting of5-(5-(4-(2-furyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-(3-chloro-4-(1,3-oxazol-2-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(4-ethyl-5-(4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(4-fluoro-5-(4-(1,3-thiazol-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-(4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-chloro-(4-(1,3-thiazol-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-chloro-4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-(3-methyl-4-(1,3-thiazol-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(4-ethyl-5-(3-fluoro-4-(1,3-thiazol-5-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;5-(5-(3-chloro-4-(2-furyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridinesulfonamide;and salts thereof.